CHAPTER
The development of a pharmaceutical oral solid dosage forms
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Rahamatullah Shaikh, Do´nal P. O’Brien, Denise M. Croker, Gavin M. Walker University of Limerick, Limerick, Ireland
1 INTRODUCTION Active pharmaceutical ingredients (APIs) are most commonly formulated and delivered to the patient in solid state forms. Among the various oral drug products available in the market, tablets are the most popular dosage form. Oral solid dosage forms consist of APIs and suitable pharmaceutical excipients such as bulking agents, binders, fillers, and disintegrating agents. These ingredients may be blended, milled, granulated, dried, tableted, or encapsulated. The successful preparation of an optimum tablet formulation is dependent upon the type of excipient added to the formulation, the corresponding product storage stability, and the powder blend properties. This chapter is therefore intended to cover two important phases in product development: preformulation and formulation. The preformulation testing discussion focuses mainly on physicochemical characterization of the API and excipients and how solubility, drug-excipient compatibility, and stability affect the chemical stability and therapeutic activity of the final drug product. Furthermore, the influence of powder characteristics of drug and excipients (particle size, particle shape, flowability, powder density) on final dosage form characteristics (mechanical properties, disintegration, dissolution) is emphasized. Processing of formulation discusses two stages, namely: process systems engineering applied to development of robust pharmaceutical processes; and manufacturing of tablets. Further, the broader goal of this work is to show the impact of process system engineering on driving down the cost and increasing process robustness and to discuss key aspects of the different methods used for tablet production. Oral solid dosage form development is an extensive topic and a thorough discussion of the topic is beyond the scope of this work. Therefore, to assist the reader’s understanding of the complexities and challenges involved, preformulation and formulation in product development have been elaborated upon.
Computer Aided Chemical Engineering, Volume 41, ISSN 1570-7946, https://doi.org/10.1016/B978-0-444-63963-9.00002-6 © 2018 Elsevier B.V. All rights reserved.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms
2 PHARMACEUTICAL PREFORMULATION AND ITS SIGNIFICANCE IN THE DEVELOPMENT OF SOLID DOSAGE FORMS The manufacturing of standard tablets requires extensive knowledge of the physicochemical properties of a drug substance/API molecule. Preformulation parameters, which determine the final dosage form and the development plan, are important. Preformulation is a stage where the physicochemical properties of the drug substance and the suitable pharmaceutical excipients are characterized. The objective of the preformulation is to choose the correct drug molecule with the correct ingredients. Preformulation also indicates the compatibility and understanding of the drug stability characteristics. Evaluation parameters are commonly used in the preformulation of drug development; these include solid-state properties, solubility, and stability (Table 1) (Carstensen, 2000, 2002; Ando and Radebaugh, 2005).
2.1 SOLID-STATE PROPERTIES Solid-state property testing includes purity, organoleptic properties, presence of polymorphs, surface properties, particle size, particle shape, flow properties, bulk density, and compression properties. These properties are very important since the Table 1 Various important parameters in preformulation Parameters Chemical analysis Identification of drug molecule Assay Purity Physicochemical properties Solubility Solvents pH Dissolution Log P pKa Physical analysis Hygroscopicity Melting point Microscopy Physicomechanical properties Pharmaceutical analysis Solid-state stability Chemical compatibility Biopharmaceutical properties
Method/analysis
UV-Vis, IR, DSC (analytical) HPLC, TLC Organic impurities, heavy metal, and in organic elements
Vehicles and extraction Salt forms, cosolvent, complexation, prodrug
Karl fisher, gravimetric, TGA, gas chromatography DSC polymorphism, hydrate, and solvent Particle shape, particle size Compaction and powder flow Temperature, humidity, and light Processing ADME
2 Pharmaceutical preformulation and its significance in the development of solid dosage forms drug stability, safety, content uniformity, and in vitro dissolution rates can be significantly influenced (Hickey and Smyth, 2011). Preformulation studies begin with the evaluation of the drug substance purity, which plays a more significant role. The purity and homogeneity of the drug substance is essential for the efficacy and safety of the pharmaceutical product. Impurities can be a result of the starting materials, synthetic intermediates, the manufacturing process or degradation products (Impurities in New Drug Substances, n.d.; RaoNageswara and Nagaraju, 2003; Grekas, 2005; Guy, 2000). Various analytical techniques are used to determine the purity of drug substances, such as differential and gravimetric thermal analysis, high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). Organoleptic properties such as color, odor, and taste are recorded for the new drug substance. If the color is undesirable, the incorporation of a dye is recommended to improve appearance of the final product. If the drug has an undesirable odor or taste, it is recommended that a suitable salt form of that drug is made. Many drug substances exist in a crystalline form (Mortko et al., 2010; Wischke et al., 2010). A crystalline particle is characterized by a definite crystal habit that relates to the external structure (such as shape and size) and a crystal lattice that describes the internal structures. A change in the crystal form (polymorph) has a significant effect on the drug particles’ mechanical properties such as particle strength, flowability, miscibility, and tablet dissolution rate and stability. Therefore, to avoid polymorphic transformation of the pharmaceutical powder during preformulation, it is important to identify any potential change in the internal and external structures of the pharmaceutical material. Various instrumental techniques are used for investigation of the solid state. These include microscopy (including hot stage microscopy) differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and single-crystal X-ray. The melting point of the APIs is directly related to the powder flow and compaction properties (Verbeek et al., 2006). APIs with low melting points often exhibit poor mechanical properties during the formulation development process (Bastin et al., 2000). Therefore, studying the physicochemical properties of APIs during preformulation development can be a pivotal method. Drug-excipient compatibility studies, which deal with the physical and chemical interactions between the drug and excipients, are important for preformulation studies. The following sections of this chapter describe how solubility, drug-excipient compatibility, and stability affect the physical, chemical, and therapeutic properties of the dosage form.
2.2 SOLUBILITY The solubility of a drug is an important preformulation property as it significantly affects the bioavailability of the drug. USP and BP classify the solubility in terms of the solvent required to solubilize 1 g of the drug at a specified temperature (Fig. 1). The solubility of the drug is usually determined by the kinetic solubility and the equilibrium solubility.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms
Solubility
Very
<1 mL
Freely soluble
1–10 mL
Soluble
10–30 mL
Sparingly soluble
30–100 mL
Slightly soluble
100–1000 mL
Very slightly soluble
1000–10,000 mL
Insoluble
>10,000 mL
FIG. 1 Description of solubility parts of solvent needed for 1 part solute (USP/NF).
DMSO Mix and incubate Buffer
Drug particles
Measure UV and LCMS techniques
FIG. 2 Representation of kinetic solubility.
Kinetic solubility is determined by firstly dissolving the drug in dimethyl sulfoxide (DMSO) and then adding water until a precipitate forms (Fig. 2) (Brittain, 2009). The samples are filtered to remove the precipitate and the concentrations are measured using UV or LC/MS technique. Kinetic solubility measurements are performed in the early stages of drug discovery and they provide a solubility trend of drug substances.
2 Pharmaceutical preformulation and its significance in the development of solid dosage forms
Drug particle Shake for 24–72 h Buffer solution Measure UV and LCMS techniques
FIG. 3 Representation of equilibrium solubility.
Thermodynamic and equilibrium solubility determine the solubility of a solid material by dissolving it in aqueous medium for a prolonged period of time until an equilibrium is achieved under constant agitation and desired temperatures (Fig. 3). This is followed by filtering the sample and analyzing the drug concentration using UV or LC/MS techniques. Thermodynamic solubility helps to identify the polymorphic and amorphous forms of the drug. Other methods of solubility analysis are pKa determination, partition coefficient, drug dissolution, and membrane permeability.
2.2.1 pKa The majority of drugs are weakly acidic or basic. Therefore based on the pH value, drugs will exist as either an ionized or an unionized species. However, unionized drug molecules are more lipid soluble and therefore will be absorbed more effectively than ionized drug molecules. The Henderson-Hasselbach equation provides an estimate of the ionization of a weak acid or base at a given pH. For acidic drugs, pH ¼ pKa + log ½ionized form=½un ionized form For basic drugs, pH ¼ pKa + log ½un ionized=½ionized form The pKa of a drug can be determined by using UV or visible spectroscopy, potentiometric titration, conductimetry, or dissolution rate method (Winfield and Richards, 2004).
2.2.2 Partition coefficient (log P) Partition coefficient (oil/ water) is an indicator of drug lipophilicity. The partition coefficient is determined by the shake flask method using two immiscible solvents, the most common hydrophilic solvent is water or phosphate buffer of pH 7.4, and for oil phase is octanol.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms The partition coefficient is defined as the ratio of unionized drug distributed between the organic phase (Corganic) and aqueous phases (Caqueous) at equilibrium. Ko=w ¼ Corganic =Ceaqueous As the Ko/w value increases, the drug’s ability to cross the biological cell membrane increases. The concentration of a compound in each phase is determined by HPLC. Since biological membranes are lipid centric, a highly lipophilic drug molecule exhibits passive absorption. However, it may have issues with low solubility. Therefore, an optimal balance between these two opposing properties is highly desirable for drug absorption (Yang et al., 2012).
2.3 DISSOLUTION STUDIES Dissolution is considered one of the most important parameters, as it provides information on the rate and extent of absorption within the human body. Dissolution is a process in which the solute of the drug substance enters into solution. The dissolution rate is defined as the rate or speed at which a drug substance dissolves in a medium. Dissolution rate of solids in a given medium under fixed hydrodynamic conditions is described by the Noyes-Nernst equation: dC ¼ k1 C s dt where k1 is the intrinsic dissolution rate constant and dC/dt is the intrinsic dissolution rate (mg cm2/s). The surface area influences the dissolution rate of the drug substance. The dissolution rate of a drug may be increased by increasing the surface area. Therefore, by studying the dissolution rate of a drug substance with a constant surface area, the intrinsic dissolution rate (IDR) can be calculated. According to modified The Noyes-Whitney equation for IDR, the dissolution rate is proportional to both solubility and surface area. dC AD ðCs CÞ ¼ dt hv where D is the diffusion coefficient in the dissolution medium; h is the thickness; A is the surface area; v is the volume; Cs is the concentration of the drug at saturated solution; and C is the concentration at particular time, t. There are two apparatus that have been used to determine the IDR, fixed-disk system (USP) and a rotating-disk system (Wood’s apparatus), which is the more commonly used system (USP and British pharmacopeia). IDR is also useful in determining the thermodynamic parameters associated with the transition between the crystalline phases. The evaluation of the dissolution rate of a drug in various dissolution media (variation of pH or use of surfactants) (Yu et al., 2004; Bartolomei et al., 2006) is an indication of the in vivo behavior of the drug.
2 Pharmaceutical preformulation and its significance in the development of solid dosage forms
2.4 STABILITY STUDIES The primary objective of stability testing is to provide various inputs for drug product development such as pharmaceutical processing, storage, and drug absorption at gastrointestinal mucosa. A preformulation stability study mainly comprises solid state, solution phase stability, physical stability, and photostability studies (Fig. 4). Solid-state stability testing is performed for solid dosage forms where the drug and excipient samples are exposed to extreme temperatures and humidity. Solid-state stability studies also provide information on possible routes of degradation, and degradation products of the drug substance. Various qualitative and quantitative analytical tools are used to detect drug degradation. A well-developed and validated stability method can be used in the latter stages, such as stability testing for clinical studies and stability testing for product license applications. Solution-phase stability studies provide information on the stability of a drug in granulating solvent and in gastrointestinal fluids. These studies include the degradation studies in 0.1 N HCl, 0.1 N NaOH, and water at 90°C, effect of pH, and oxidation studies. The application of appropriate testing will provide important information to formulation scientists on various factors that will affect product stability, potential compatible excipients, and preferred storage conditions (Di and Kerns, 2003; Chen et al., 2006).
Stability studies
Physical stability
Chemical stability
Appearance Palatability Uniformity Dissolution and Suspendability
Photolytic stability UV light (254 and 360 nm) for 2–4 weeks
Solid state stability
Liquid phase stability
Temperature (5, 25, 40, and 50°C) Humidities (RH) (0%, 31%, 53%, and 75%) Oxidative (oxygen along with accelerated heat)
Oxidation Hydrolysis pH 1, 3, 5, 7, and 9 at 37°C
FIG. 4 Flowchart describing various types of stability and conditions used for preformulation.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms
2.5 DRUG-EXCIPIENT COMPATIBILITY STUDIES Studies of possible drug-excipient interactions are an important phase in preformulation development. Commonly used excipients in solid dosage forms are binders, fillers, disintegrants glidants, lubricants, and diluents. The potential physical or chemical interactions between drug and excipient may affect the chemical nature, therapeutic activity, and stability of the dosage form (Bharate et al., 2010). Therefore, knowledge of possible drug-excipient interactions is important in selecting the suitable excipient. There is adequate information available on known drugs. However, in compatibility studies for new drugs or excipients, the preformulation scientist must produce the required compatibility data. The desired ratio of drug to excipient used in drugexcipient compatibility studies is usually 1:1, but can be subject to the ratio required in the final formulation. Required ratios of drug to excipient are kept in glass vials and then subjected to 50°C and 80% RH for the duration of 1 month (Budura et al., 2011). The analytical techniques used for studying the physical and chemical properties of possible drug-excipient interactions include: thermal analysis (DSC, DTA), spectroscopic methods (X-ray diffraction, FT-IR, NMR), and chromatographic methods (HPLC, LC-MS) (Rus et al., 2012; Gibson, 2009). Compatibility studies between drug and excipient will provide information on the efficacy, safety, and stability of the drug product.
2.6 PHYSICAL PROPERTIES OF PHARMACEUTICAL SOLIDS The journey from chemical molecule to tablet medicine involves the isolation of the active pharmaceutical ingredient as a solid, and the combination of this solid with additional solids at different processing stages. As a result, the physical properties of pharmaceutical solids are central to the handling, processing, and performance of oral solid dosage forms. Some solid-state properties are obvious and easy to measure: particle size, shape, crystal form. Others remain elusive: the concept of “stickiness” for example. This is a broad topic and only a number of elements are treated at a high level here. Where necessary the reader is referred to additional text for supplementary details. Particle size describes the size of an individual particle. For bulk powders, there will be a distribution of particle sizes contained in the powder, and this is described as particle size distribution or PSD. Most materials are produced to a defined particle size distribution specification, meaning they need to meet some size requirement. Particle size distribution is one of the most common characterization techniques for bulk powders and yet one of the most difficult. There is the issue of representative sampling: can you be sure the sample is indicative of the bulk powder? Different measurement techniques exist: sieving, image analysis, laser diffraction. Each will almost always give slightly different results. This is due to variations in the principle of measurement. Further information is best quoted directly from equipment manufacturer’s literature.
3 Drug product manufacturing
Particle shape describes the external appearance of a solid particle. Shape is inherently linked to the underlying crystal structure, but can also be impacted by solvent or impurity interactions, and processing conditions. Particle shape can impact handling and processing of materials, material flow and compaction. Particle shape is easily assessed with microscopy or other visual methods. Most pharmaceutical solids are crystalline, that is the internal structure of the solid consists of a regular repeating array of atoms. Polymorphism is a wellrecognized phenomenon whereby a pure chemical compound may exist in two or more structural orientations. As different polymorphs display individual physical properties such as density, melting point, and solubility, polymorphism is vitally important to the manufacture of chemicals, in particular, pharmaceuticals. Production of an unwanted polymorph will give a drug formulation that most likely will not satisfy the product requirements. X-ray diffraction is the standard technique for identifying polymorphic form as it directly analyzes crystal structure, but methods such as infrared and Raman spectroscopy can also be suitable (Rolf, 2006). The flowability of bulk powders is traditionally defined as “The ability of the divided solids to flow under specific settings in a defined condition” British Pharmacopeia (2010). Bulk powder flowability is inherently important to the manufacturing environment as material must be transferred into/out of unit operations. Poorly flowing solids can block orifices and transfer lines, and cause rat holing and segregation. Accurate measurement of flow properties remains challenging and again the reader is referred onwards (Prescott and Barnam, 2010). Powder density is an important physical property as it represents how much space a mass of powder will occupy, how much will fit in product containers, etc. The bulk density of a material is the ratio of the mass to the volume of an untapped powder sample. The tapped density is obtained by mechanically tapping a graduated cylinder containing the sample until little further volume change is observed. The difference between the bulk and tapped density is a result of the interparticulate interactions in a given powder and can be indicative of powder flow and compressibility properties. A compressibility index and Hausner ratio can be quantified from density measurements as per the equations below. Vo and Vf represent bulk and tapped densities, respectively. Compressibility index : 100 Vo Vf =Vo ; Result < 15 indicates good flow properties Hausner ratio : Vo =Vf ; Result close to 1 indicates good flow properties
3 DRUG PRODUCT MANUFACTURING Oral solid dosage forms are the most common route of drug delivery. Oral dosage forms generally offer the most convenient and safe route of administration. Solid dosage forms may be administered as tablets, capsules, powders, and cachets.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms Table 2 Advantages of tablets Tablet manufacturing High-dose precision and less content variability High Chemical and microbial stability Large-scale production Lowest in cost Can be coupled with sustained or controlled release profiles Cheap and easy of packaging Easy of shipping and dispensing Patient Easy for administration Blandness of taste Portability Affordability
Tablets and capsules are the most widely manufactured and prescribed oral dosage forms. Tablets offer various advantages over other dosage forms (Table 2). Tablets are solid pharmaceutical dosage form containing drug substance with or without suitable pharmaceutical excipients. Tablets vary in shape (round, oval, oblong, cylindrical, elliptical, etc.) and differ greatly in size and weight, depending on amount of drug substances present and the intended method of administration. Shape and size of the tablets may influence patience compliance. Studies suggest that tablet sizes greater than approximately 8 mm in diameter present swallowing difficulties in patients (www.fda.gov/downloads/drugs/.../guidances/ucm377938.pdf). Oval tablets may be easier to swallow and have faster esophageal transit times than round tablets of the same weight (www.fda.gov/downloads/drugs/.../guidances/ucm377938.pdf). Tablets are generally manufactured by two methods: compression or by molding. Mostly large-scale production methods are used for production of compressed tablets, while molded tablets involve small-scale production. The various tablet types are listed in Table 3. Apart from active pharmaceutical ingredients, tablets also contain various inactive pharmaceutical excipients, which have been added during manufacturing. Excipients are used as protective agents to aid the API manufacturing process and to improve drug absorption. Pharmaceutical excipients play a vital role in formulation development; hence, it is necessary to select a suitable excipient (which satisfies the ideal characteristics of the formulation) and its relative concentrations in the formulation. The ideal properties of a pharmaceutical excipient are given as • • • •
Pharmacologically inert Physical and chemical compatibility Nontoxic Microbiological stability
Table 3 Classification of tablets Type of tablet
Description
Compressed tablets
Standard uncoated tablets are formed by compression (using powdered, crystalline, or granular active materials (API), with or without appropriate excipients). These are compressed tablets containing a sugar coating.
Sugar-coated tablets Film-coated tablets Multiple compressed tablets Enteric-coated tablets Controlled release tablets Effervescent tablets Chewable tablet
Buccal and sublingual tablets Lozenges and troches
These are compressed tablets containing a water-soluble polymers coating. These are compressed tablets made by more than one compression cycle in the same tablet ex two-layer and three-layer tablets. These are compressed tablets coated with gastric fluid resistance substances. Compressed tablets, which release the drug slowly over a desired period of time, e.g., delayed release, extended release, and sustained release. Effervescent tablets consist of an organic acid and a carbonate salt along with API, taken in water and produces effervescence. Tablets are intended to chewed and swallowed.
Vaginal tablets
These tablets are placed under the tongue (sublingual) or in between gums and cheek (buccal) for the fast and slow release of the medicament. These are strong slowly dissolving tablet formulation in mouth and throat. These tablets are prepared by compression (troches) or candy molding process (Lozenges) to produce local or systemic action. These are wide or pear shaped and prepared by compression.
Molded tablets
These are dispensed using a tablet triturate mold.
Dispersible tablets
Uncoated or film-coated tablets added to water to form a suspension before administration.
Significance
To mask the taste and odor, and to protect the formulation from oxidation. To protect the drug substance from atmospheric conditions. To separate physically or chemically incompatible ingredients, to produce prolonged or repeated release profile. To protect the drug substances, which are inactivated or destroyed in the stomach. Improved patient convenience and compliance.
To improve the formulation taste, and acts faster absorption. To be given to the children or elderly patient who is having difficulty in swallowing, water not required for swallowing so can be taken at any time and in any place. Suitable for those medications who does not absorb very well in the stomach and for quicker drug absorption. Better patient compliance Avoid first pass metabolism.
Easy of admission than creams or ointment Increased drug levels at systemic circulation. It can be extemporaneously prepared, molded, and compressed tablets according to the requirement of patient. Dose titrations adjustment for children less than 5 years.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms • • • • • • •
Good organoleptic properties Good material properties (flow and compaction properties) Economical Readily available No negative effect on drug bioavailability Compatible with primary packaging materials Regulatory agencies acceptability
Pharmaceutical excipients are classified according to function they performed. Commonly used excipients in tablet formulation are given in Table 4.
3.1 DILUENTS Diluents are used to increase the size of the dosage form. Diluents are usually added to tablets where the active constituent is in low dose and to improve the powder flow and compaction properties prior to direct compression. Diluents are commonly used in the range between 5% and 80%. A good filler should be chemically inert, nonhygroscopic, have good flow and compaction properties, be water soluble, have pleasant taste, and be cost effective. Commonly used diluents are lactose, microcrystalline cellulose-Avicel (PH 101 and PH 102), calcium phosphate, starch. Lactose is used in hydrous and anhydrous forms: anhydrous lactose is used in direct compression and lactose monohydrate is used in wet granulation process. Although lactose is an inert filler, it is unsuitable for people with lactose intolerance. Microcrystalline cellulose is highly compressible and more extensively used for direct compression. It also exhibits disintegrant activity and binder activity. Calcium phosphate is used both as wet granulation and direct compression. However, it was observed that it interferes bioavailability of tetracycline tablet (Satoskar et al., 2015).
3.2 BINDERS In order to manipulate flow property and compressibility, binders are added to tablet formulation. Binders are generally added either in solution or dry powder form. The most common method of adding binders is solution binders that are prepared beforehand in suitable solvent (water or alcohol) and added during mixing. Polymeric binders are usually hydrophilic in nature; spreading of a hydrophilic binder over particle surfaces can aid dissolution of poorly soluble drug by increasing the wettability. However, excess concentration of binders leads to negative effect on tablet disintegration and dissolution rate. Apart from binder concentration, several other factors could significantly affect the granules particle size range and granules hardness such as, viscosity of binder, solvent quantity, solvent addition method (open tube or spray), and solvent rate. Hence ,optimization of these parameters is extremely critical for a successful wet granulation process. Dry binders are added to the powder blend during dry granulation or direct powder compression process. However, it has been observed that binders tend to lose tensile strength after the two mechanical
Table 4 Commonly used excipients in tablet formulation (Liberman et al., 1989) Excipient category
Function
Examples
Binders
Substances that promote cohesiveness of powders thereby providing the mechanical strength to the tablet.
Diluents
Inert substance used as filler to provide the required bulk of the tablet and it also provides better tablet properties.
Lubricants
A lubricant, an additive to reduce friction during tabletting. It also helps tablet to overcome of various defects like lamination, sticking, and chipping.
Glidant
Glidants are usually used to improve powder flow properties of the formulation.
Disintegrant
Disintegrants are used in solid dosage forms to break up a dosage form after oral administration; hence, it contributes to increase in surface area and thereby faster dissolution.
Coloring agents
Colors are added to impart color to the formulation to identify new formulation and ultimately to increase the patient compliance.
Flavors
Flavors are incorporated into formulation to mask the unpleasant tasting API.
Carboxymethylcellulose Methylcellulose Povidone Water soluble (lactose, sucrose, and sorbitol). Water insoluble (microcrystalline cellulose, starch, calcium phosphates). Magnesium stearate Magnesium lauryl sulfate Stearic acid Calcium stearate Talc Aerosil Calcium silicate Sodium starch glycolate Croscarmellose sodium Starch Crospovidone FD&C Red 33 Iron oxide—red Iron oxide—yellow FD&C yellow Syrups Menthol Clove oil
Typical percent 2%–8% 1%–5% 2%–8%
0.2%–2.0% 1%–3% 0.25%–2% 0.5%–4% 1%–5% 0.1%–0.5% 0.5%–2% 2%–8% 1%–5% 5%–10% 1%–5% 0–0.75 mg 0–0.5 mg 0–0.5 mg
Continued
Table 4 Commonly used excipients in tablet formulation (Liberman et al., 1989)—cont’d Excipient category
Function
Examples
Coating materials
A tablet coating is a covering over a tablet to protect drug from environment (oxygen or humidity), to mask taste or odor of drug substance, modifying release drug release profiles.
Adsorbent
Adsorbents are used into formulation to adsorb the semisolid or liquid excipients.
Antioxidant
Antioxidants are added to tablet formulation to delay or inhibit the oxidation process.
Sugar coating: liquid glucose Film-coating polymers: methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose Enteric-coating polymers: cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate Magnesium oxide Kaolin Bentonite Ascorbic acid Propyl gallate Sodium ascorbate Sodium bisulfite
Typical percent
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treatments (roller compaction/direct compression) (Tapper and Lindberg, 1986; Holm, 1997). This phenomenon is best described as work hardening (Malkowska and Khan, 1983). Therefore, selecting the binder for direct compression is very important with regard to tablet hardness.
3.3 DISINTEGRATING AGENTS Disintegrating agents are considered important excipients, which facilitate the breaking of the dosage form when it comes in contact with GI (gastrointestinal) fluid. The disintegrating agent assists the onset of dissolution and subsequently provides for faster drug absorption. Disintegrants are classified into disintegrants (microcrystalline cellulose, colloidal silicon dioxide, alginate, and starch), and superdisintegrants (crospovidone sodium, starch glycolate, and croscarmellose sodium). Superdisintegrants have recently been developed to improve the disintegration processes and result in tablets, which swell up faster at relatively low concentrations and possess superior powder compression properties than normal disintegrants. Disintegrants can be added by three methods: intragranular (before granule formation), extragranular (before the tablet compression), and both (intragranular and extragranular addition). Swelling, porosity, capillary action (wicking), and deformation have been the main observed mechanisms of disintegration (Bele and Derle, 2012). Factors that can affect performance of disintegrants include particle size, compression force, method of addition, and moisture content. In addition, it has been shown that performance of disintegrants can be altered significantly when mixed with various excipients. Excipients can influence disintegration due to the amount of hydrophobic lubricant, the quantity of binder, and hydrophobic coating. Hence, care must be taken to optimize the formulation. Generally, disintegrants are hygroscopic in nature and if it absorbs moisture from the air there is a potential to impair the stability of the formulation. Thus, for moisture-sensitive drugs, adequate packaging protection should be provided.
3.4 LUBRICANT Pharmaceutical lubricants are used to improve powder flow properties and to reduce friction during tabletting. They also help the tablets to overcome various defects like lamination, sticking, and chipping. Lubricants are added to oral solid formulations in a range of 0.25%–5.0%, w/w. Lubricants are mainly divided into three categories, glidants, antiadherent excipients, and die-wall lubricant. Glidants are usually added prior to compression to improve the powder flow properties of the materials by reducing friction between particles. The second class of lubricant activity is the antiadherent, which prevents the adhesion between the tablet surfaces and tablet punches. Die-wall lubricants reduce friction between the tablet surface and the die wall during tablet compaction and tablet ejection. Commonly used types of lubricants are listed in Table 4. Talc is the most commonly used glidant, which is also used as an antiadherent. High concentration of talc may lead to reduction in the rate
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms of dissolution. Therefore, the lubricant amount should be kept below about 1%. Magnesium stearate is a boundary lubricant, most commonly used as a lubricant and to a lesser extent, as a glidant and antiadherent for tablet manufacturing practice. Magnesium stearate is relatively inexpensive, has a high melting point, and is chemically stable (Morin and Briens, 2013). Although magnesium stearate is an excellent lubricant, it can pose a negative effect on delayed drug dissolution (forms a hydrophobic coating on the particles of blend), tablet hardness, and batch-to-batch variation of lubrication. The U.S. Pharmacopeia (USP) states to use single source of magnesium stearate for all batches production (Niazi, 2009).
3.5 COATING MATERIALS Tablet coating is the process where coating material is applied to the surface of the tablet to achieve the desired properties of dosage form over the uncoated variety. The advantages of coating are listed below. • • • • • •
Improving taste, odor, and color of the drug Improving ease of swallowing by the patient Improving product stability To protect against the gastric environment To improve mechanical resistance of the dosage form Modifying release properties
There are three main processes for tablet coating: sugar coating, film coating, and enteric coating. Various classes of pharmaceutical coating materials used in tablet coating depending on the phase of coating are reached. Coating materials can be categorized as follows: • • • •
Binders (acacia, gelatin, cellulose derivatives) Fillers (calcium carbonate, titanium dioxide, talc) Colorants (dyes, iron oxides, titanium dioxide) Antiadhesives (talc)
3.5.1 Sugar coating Unlike film coating, sugar coating is a more laborious multistep process, leading to final tablet weight increases of up to 30%–50%, significantly increasing tablet size. The process of sugar coating involves various steps, i.e., sealing, subcoating, smoothing, coloring, and polishing.
Sealing A seal coat is applied over the tablet core to protect against water penetration into the tablet from the sucrose coatings to follow. Hence, it offers good stability of product and can also strengthen the tablet core. Sealing coat consists of Shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hyroxylpropyl cellulose, hyroxypropyl methylcellulose (HPMC), and Zein (a corn protein derivative).
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Shellac was previously used as a sealant. However, this has largely been replaced by zein CAP and PVAP due to polymerization problems. The amount of sealing coat material depends on tablet porosity and batch size; hence, optimizing the quantity of sealing coating applied is very important to ensure tablet cores are sealed effectively.
Subcoating Subcoating is performed to round the tablets edges. In this process, there is a significant increase in tablet weight. Generally, lamination process and suspension process methods are used for subcoating. In lamination process, the subcoat mixture consists of sucrose and binder solution such as acacia or gelatin, which is applied over the tablet surface followed by powder containing materials such as calcium carbonate, titanium dioxide, calcium sulfate, and talc. Finally, drying air is applied in order to evaporate the water. During the suspension process, a suspension of fillers in gum solution is applied. After that, sucrose solution is applied followed by drying. Suspension process is suitable for automatic methods.
Smoothing Smoothing process is applied in order to smooth out subcoated rough surfaces and to increase tablet bulk to desired size. Smoothing syrup generally consists of 60%–70% sugar solid. In some cases, however, syrup also comprises acacia, gelatin, pigments, starch, or opacifier. Smoothing is performed many times (about 10 cycles), until tablets are suitable for the next (coloring) phase.
Coloring Coloring phase is a significant step in sugar-coating process, which gives the tablet improved appearance and stability. Sugar-coating solution consists of 70% syrup and other coloring pigments. Previously water-soluble dyes (coloring agents) were mainly used as for sugar-coated tablets. However, water-soluble dyes are generally associated with color migration problems, and dyes usually transfer to the surface of the tablets during drying. Hence, the use of water-insoluble pigment (lakes) has now replaced the dyes, which provides even tablet color and maintains batch-to-batch color uniformity.
Polishing Generally sugar-coated tablets are dull in appearance; polishing gives the characteristic surface shine and tablet elegance. Polishing is performed in polishing pan using the beeswax, carnauba wax, and candelila wax mixture.
3.5.2 Film coating Film coating is single-stage coating process and needs a relatively short time and so is favored over sugar coating. Film coating is the deposition of a thin film of polymer (between 20 and 100 μm) applied mainly to tablets; in addition, film coating can also be applied to hard and soft gelatin capsules and multiparticulate system.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms Film-coating formula generally consists of polymers, plasticizer, colorants/opacifiers, solvents, etc. Table 5 depicts commonly used film- and enteric-coating materials. The film-coating process involves spraying of a coating solution onto a tablet bed in pan coater followed by immediate drying to form a thin, even film on the tablet surface. Usually, three main methods of coating are used, i.e., modified conventional coating pans, fluid bed equipment, and side-vented pans. Film formation and coating uniformity can be influenced by the following process parameters: method of atomization of the coating suspension, method of moving the tablet bed that ensures that all tablets are sufficiently mixed and agitated, and finally, adequate heat input to provide rapid drying of the applied coat. In addition to process parameters, tablet Table 5 Commonly used film and enteric-coating materials Ingredient category
Function
Examples
Polymers coating
Film-coatings polymers are used to improve product appearance and to protect the drug substance from atmospheric conditions.
Entericcoating polymers
Enteric-coating polymers are pH-sensitive polymers, they are insoluble at acidic pH (stomach) but soluble at basic pH (small intestine); enteric-coating prevent tablet core disintegration in the stomach.
Hydroxyproply methyl cellulose (HPMC) Methyl hydroxyethyl cellulose Ethylcellulose Povidone Acrylate polymers (Eudragit L and Eudragit S) Hydroxypropyl methylcellulose phthalate (HPMCP) Polyvinylacetate phthalate (PVAP) Water Methanol Ethanol Acetone Polyethylene glycols PEG (200–6000) Glycerol Castor oil Triacetin Insoluble pigments Titanium dioxide Silicate
Solvents
The function of the solvent in film-coating formula is to convey coating materials to the tablet surface or pellets.
Plasticizers
Plasticizers are added to filmcoating formula to improve the flexibility and processability polymer film.
Colorants/ opacifiers
Colorants/opacifiers are added to film-coating formula to improve product appearance and to protect the drug against light.
Miscellaneous agents
Flavors, sweeteners, antioxidants, etc.
Solubility profile
Above pH 6.0
Above pH 4.5
Above pH 6.0
4 Manufacturing methods for oral solid dosage form
properties (e.g., size, shape, porosity, hardness, density, pan loading, etc.), as well as equipment specific parameters (e.g., pan diameter, geometry, baffle configuration, etc.) all significantly impact the coating quality.
4 MANUFACTURING METHODS FOR ORAL SOLID DOSAGE FORM Tablet formulation methods can be divided into two groups, direct compression and granulation. There are a number of other novel granulation methods available to pharmaceutical manufacturers, but these are used less frequently, i.e., pneumatic dry granulation (PDG), melt granulation, foam granulation, moisture-activated dry granulation (MADG), spray-drying granulation, extrusion granulation. Choosing the optimum formulation method is important because the final tablet performance will be dependent on method of tablet manufacturing. Hence, the process selection is based on thorough knowledge of chemical properties of the drug and excipients, their compatibility in the formulation, its ability to flow, and finally its release properties. API characteristics, such as the melting point, moisture/temperature sensitivity, flowability and compressibility/compactability, are critical parameters in determination of a suitable formulation method. API characteristics and their preferred tablet formulation methods are given in Table 6. In the pharmaceutical industry, selection of a particular manufacturing method is often based on individual experience; for instance, for any given API compound, different industries can have very different approach. This section will focus on the importance of granulation in the production of oral dosage forms and the main advantages and disadvantages of each technique. Oral solid dosage forms unit operations are determined according to which manufacturing techniques been applied. This includes: feeding, blending, milling granulation, drying, compression/encapsulation, and coating. A typical primary unit operation matrix in oral solid dosage form is shown in the schematic flowchart (Fig. 5). In Section 5, detailed reviews on all key unit operations associated with tablet manufacturing process are discussed. This is a broad topic; therefore, the process described here simplifies processing of the formulations, and those interested in studying the subject area further are encouraged to refer additional text for supplementary details and texts listed in the reference section. Table 6 API characteristics and corresponding preferred tablet formulation methods API characteristics and release profiles
Suitable granulation technique
Soluble and amorphous Sensitive to moisture Insoluble and crystalline Poor flowability Poor flowability and compressibility Controlled release
Wet or dry granulation Melt granulation Melt granulation and/or spray drying Slugging and roller compaction Fluid-bed granulation Fluid-bed granulation
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms Dispensing API
Excipients
Blending Direct compression
Granulation
Filling
Locking
Dry granulation
Wet granulation
Milling
Milling Drying
Lubrication
Blending
Tabletting
Coating
Capsule
Packaging
FIG. 5 Typical manufacturing process of solid oral dosage forms.
4.1 DIRECT COMPRESSION (SHANGRAW ET AL., 1989) The term direct compression (DC) is defined as the process by which tablets are compressed directly from powder blends of API with the excipient and the lubricant. DC does not involve premechanical treatment of the powder apart from powder mixing, which makes the product easy to process. Following unit operation is involved in direct compression i. Milling of APIs and excipients ii. Mixing of APIs and excipients and iii. Tablet compression
4 Manufacturing methods for oral solid dosage form
Feeders are also needed for continuous manufacturing. Advantages of direct compression: The main advantage of DC is that it is economical. DC requires only three unit operations steps, reducing the number of unit operations required, resulting in less process validation, and lower energy consumption. Batch-to-batch variation is negligible. DC process is ideal for moisture or heat-sensitive APIs due to elimination of moisture and heat treatment. Furthermore, the tablet will also pose good hardness and friability. Disadvantages of direct compression: The main limitation of DC is that it cannot be used for all APIs. For high-dose APIs, its challenging to formulate if the API does not have appropriate flow and compaction properties. In the case of very low-dose APIs, it is difficult to achieve desired uniformity and homogeneity in the tablet formulation. APIs poor flowability depends on many powder characteristics such as particle size, shape, and size distribution that can be modified by particle engineering. Segregation can be reduced by careful selection of excipients and ordered mixing. Therefore, formulation should be designed to accommodate the limitations imposed by the API s such as flowability and segregation. DC excipients can be high cost due to a high requirement on the excipients used for DC.
4.2 GRANULATION If a powder blend cannot be compressed directly into tablets, the formulator will turn to granulation processes to increase the flowability and decrease dustability. Granulation processes are extensively used in the manufacturing of oral solid dosage forms. Granulation is a technique of particle enlargement by agglomeration. Granulation offers various advantages and the reasons for granulation are listed below (Lieberman et al., 1989). • • • • • • •
To To To To To To To
improve the flow properties of the powder blend. narrow the particle size distribution of the powder blend. improve the compactability of the powder blend. increase the density the powder blend. prevent the segregation. increase the uniformity and homogeneity of the tablet. control the rate of drug release
Granulation processes can be classified into dry granulation or wet granulation.
4.2.1 Dry granulation The dry granulation process is suitable for APIs that are sensitive to solvents, heat, and moisture. Dry granulation process offers better flexibility than direct compression and is more cost effective than wet granulation because it does not require heat
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms or moisture. Dry granulation can be performed by roller compaction and slugging methods. This process involves mechanical compression (slugs) or compaction (roller compaction) of powder mixture with binder to facilitate the particle agglomeration (Hancock et al., 2003; Lieberman et al., 1989). Following unit operations are involved in dry granulation: 1. 2. 3. 4. 5. 6.
Milling of APIs and excipients to delump the powders Blending of powder mix Compression into large, hard tablets (slugs) or ribbons Milling of slugs or ribbons to produce desired particle size Mixing with lubricant and disintegrating agent Tablet compression
Feeders are also needed for continuous manufacturing.
4.2.2 Wet granulation The most commonly used method of tablet manufacturing is wet granulation (Almaya, 2009). Wet granulation is achieved by wet massing of the API and excipients with granulation liquid (with or without polymeric binder), followed by wet sizing and drying. Wet mixing is usually performed with water, but in some cases other solvent (ethanol) are also used (Parikh, 2005). Following unit operation involved in wet granulation 1. 2. 3. 4. 5. 6. 7.
Milling of APIs and excipients Mixing of powder mix Agglomeration (mixing of solution binder with powder mix) Drying of moist granules Milling of dry granules with lubricant, disintegrant, and dry binder Mixing of screened granules with lubricant, disintegrant, and dry binder Tabletting
Feeders are also needed for continuous manufacturing. Advantages of wet granulation: A large number of pharmaceutical drugs are formulated using a wet granulation process. It improves the bulk density and flowability of the powder mix. Wet granulation prevents segregation of APIs by improving mixing homogeneity. Homogeneous color distribution can also be obtained. Fine or dusty powders can be handled easily. The compressibility of powders is improved due to addition of polymeric binder solution. It improves the dissolution of hydrophobic drug (Lieberman et al., 1989). Disadvantages of wet granulation: Due to multiple unit operations, it requires many expensive equipment and a large space. It is a time-consuming and complex process (wetting and drying). Furthermore, drying phase makes the wet granulation process more expensive (most energy-intensive operation). Moisture and heat-sensitive APIs are not suitable with wet granulation method.
4 Manufacturing methods for oral solid dosage form
Wet granulation uses various methods of producing granules based on certain situations. However, high shear granulation and fluid bed granulation methods are more frequently used. High shear mixture granulation (Gokhale et al., 2005). High shear granulators contain a cylindrical or conical vessel, a chopper, a jacket, heating and cooling control system. High shear granulation is performed in closed container that involves mixing, spraying of binder liquid on powder bed using a spray nozzle, granule attrition, and breakage followed by drying. Following process variable may affect the granulation process • • • •
Impeller and chopper speed Load of the vessel Granulating solution addition rate and method Mixing time
Advantages • Short granulation time • Highly viscous materials can be handled • Less amount of binder solution is required • Granulation end point is predictable Disadvantages • Mechanical degradation (fragile particles) • Not suitable for thermolabile powders • Overwetting can lead to larger granules Fluidized Bed Granulation (Parikh and Mogavero, 2005). Fluidized bed dryer contains air-handling unit, product container, air distributor, exhaust fan, control system, solution delivery system, and spray nozzle. In fluidized bed granulation process initially, a powder mix is fluidized in heated air, spraying of liquid binder onto the fluidized powder bed occurs, followed by drying. Following process factors affect fluidized bed granulation • • • •
Fluidizing air flow rate/gas velocity Liquid binder spray rate Atomization air pressure Inlet process air temperature
Advantages • Offers continuous drying • Wet screening is not required • Suitable method for subsequent coating and controlled release products Disadvantage • Problems with reproducibility
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms
5 TYPE OF UNIT OPERATION
5.1 PHARMACEUTICAL PROCESS DESIGN METHODOLOGY Unit operation design depends on the requirements for the process step. These are driven by product performance targets such as composition, storage properties, and moisture content. Traditionally, pharmaceutical process development has been based on the deployment of known technologies according to previous practice for each given process step. Basic design and sizing is done to ensure the chosen unit operation is fit for purpose and operational parameters are derived/refined from test batches. Such an approach, while well developed, results in long commissioning times for each new process. Additionally, it generates significant amounts of off-specification material during commissioning and testing. While some of this material may be suitable for reprocessing, a certain amount will be lost during this activity. Product quality is achieved as the result of empirical adjustment of process parameters based on testing of manufactured material. This empirical approach is limited in its ability to inform future process design. An alternative approach, which is now gaining traction in pharmaceutical manufacturing, is Quality by Design (QbD). Under this approach, product quality is considered from the start of process development and is fundamental to all design decisions. QbD emerged from the realization that many quality problems in manufacturing resulted from the design of the product, particularly where the design included difficult-to-manufacture elements. QbD was a recognized principle in manufacturing by the early 1990s, but it has taken longer for the pharmaceutical industry to adopt it. The goals of QbD in pharmaceutical manufacturing can be summarized as (Yu et al., 2014): • • • •
To achieve meaningful product quality specifications that are based on clinical performance To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control To increase product development and manufacturing efficiencies To enhance root cause analysis and post approval change management
These goals are achieved by linking product quality to clinical performance and designing the process to deliver this. In seeking to optimize pharmaceutical oral solid dosage forms, it is necessary to consider the capability of tablet manufacturing unit operations to deliver the pharmacist’s chosen properties. Unit operations that are important in oral solid dosage preparation are: • • •
Crystallization Drying Size reduction
5 Type of unit operation
• • • • •
∘ Milling ∘ Screening Blending Granulation Compaction Coating Encapsulation
Not all of these unit operations will be utilized in a given preparation, and the process designer should endeavor to include the minimum number of unit operations possible. Thus, some of the discussion will focus on how particular unit operations can be optimized to avoid additional processing further downstream. Traditionally, pharmaceutical manufacture has favored batch production and these processes are well established for that mode of production. In recent years, continuous production has been investigated in pharmaceutical manufacture for a number of reasons: reduced cost, reduction of production volumes, less variation in product quality. Continuous manufacturing will be discussed at a later stage within this chapter.
5.2 UNIT OPERATION DESIGN Before discussing specific operations, it is useful to take a brief overview of unit operation design (Fig. 6). Any given unit operation involves a physical piece of equipment designed to achieve one or more physical and/or chemical transformations. Design of a unit operation is based on application of relevant fundamental scientific principles in conjunction with an engineering concept to create a piece of technology to achieve a specific transformation. For example, design of a reactor will involve the application of reaction thermodynamics, heat and mass transfer, and fluid
Equipment model
Product specification
Physicochemical models
Unit operation
FIG. 6 Unit operation design elements.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms mechanics in conjunction with a reactor design concept (e.g., CSTR) to deliver a reactor capable of undertaking a specified reaction. To deliver the design, the engineer must first select the most suitable concept for the desired process step. This concept will come with design equations and/or rules that must be applied. The next step is selection of suitable physicochemical principles to model the behavior of the desired operation. Each of these will again come with governing equations, or rules of thumb. The engineer must now combine these equations and rules into a coherent analysis from which a design can be generated. In order to accomplish this, fundamental data about required inputs and outputs are needed. Outputs are generally product (or intermediate) specifications, while inputs cover the set of data required by the analysis to generate a solution. In practice, many of the unit operations for oral solid dosage formulation arrive as complete pieces of equipment from suppliers. Equipment selection is done from supplier catalogues according to desired processing concept and required product throughput. Furthermore, in a mature pharmaceutical production facility, there will be a range of existing unit operations available for use on a new process, which the engineer may be obliged to use rather than purchasing new equipment. The selected equipment will have a range of operating conditions within which it can operate to produce particular product characteristics. The engineer’s task is to select a suitable set of operating conditions based on knowledge of desired product characteristics and equipment behavior. To specify the optimum operating parameters, the engineer must determine the relationship between the various inputs and the desired product characteristics, while remaining vigilant for undesired output behaviors. For control purposes, it is necessary to identify which inputs have the most impact on output behavior: the control recipe must take special care to control these parameters. These relationships can be difficult to establish analytically, and where such an analytical relationship might be established, its solution for any practical technology is infeasible. Thus, these relationships must be derived empirically at laboratory or pilot scale. By choosing suitable lab- or pilot-scale analogues of the unit operation, devising appropriate experiments, and using multivariate data analysis, meaningful relationships between input and output variables can be established and used to design the unit operation for production.
5.2.1 Crystallization The range of equipment concepts for crystallization is broad and a thorough discussion of the topic is beyond the scope of this work. The reader is encouraged to study the literature on the topic before undertaking design of a crystallization operation. The design variables for crystallization process are shown in Fig. 7. The desired output from crystallization is a specified particle size distribution (PSD) and crystal form. Inputs will be solution or slurry concentration and temperature. The key
5 Type of unit operation
Nucleation and growth kinetics
Solubility Desired PSD and crystal form
Process temperature control
Slurry concentration and temperature
Agitation
FIG. 7 Design variables for crystallization.
process variable is temperature, but agitation is also a factor. The key physicochemical model involved is the kinetics of crystal nucleation and growth. The underlying principle behind crystallization is to encourage precipitation of solid material from solution by adjusting the solubility of the solute. The state under which this occurs is known as supersaturation, where the solute concentration exceeds the solubility for the prevailing conditions. Knowing that solubility is a function of temperature and concentration, supersaturation is typically achieved in three ways: • • •
Evaporation of solvent to increase solute concentration (evaporative crystallization) Reduction of solution temperature to reduce the solubility limit (cooling crystallization) Addition of a second solvent to the solution to reduce solubility (antisolvent crystallization)
It is up to the designer to choose the method most appropriate for the operation under consideration. Crystallization can be batch or continuous. In continuous operation, care must be taken in moving the slurry through the process to avoid mechanical damage to the crystals and prevent fouling and blocking of equipment lines. Process analytical technology (PAT) has become key to monitoring and controlling crystallization
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms processes: online particle size analysis tools allow the process to be controlled based on extent of particle growth achieved rather than on estimations of process progress. Variation of temperature will result in variation of crystal size and form and so it must be avoided. Agitation can be used to maintain consistent heat exchange within the slurry. If the kinetics of nucleation and growth are such that each is optimized at a different temperature, the designer should consider operating two crystallizers in series to achieve optimum performance. With this arrangement, care must be taken to control the temperature of the transfer lines so that crystallization and sedimentation does not occur in them.
5.2.2 Filtration and drying Filtration, washing, and drying are the steps that follow crystallization to give a dry powder form of the pure API. The goal is to remove the solvent used for crystallization. There are two key reasons for this: • •
Solvents used in the process may not be safe for human consumption (primary) Wet powders can be difficult to handle during the formulation and tabletting process
There is a wide range of technological solutions available for both filtration and drying; it is not uncommon to see the two operations combined into a single unit. A thorough discussion of the various technologies is not possible here, but it is possible to outline the general design principles for the step. The design variables for filtration operation are shown in Fig. 8. The key output parameter is the acceptable moisture content in the final powder: the extent to which the solvent has been removed from the crystalline material. This can be quantified by loss-on-drying analysis (LOD) where a known quantity of the wet material is dried quickly and mass balance used to calculate the moisture content. PSD of the resulting powder is also an important metric: if the PSD achieved during crystallization is adversely affected at this step, then further downstream processing may be required to restore the desired PSD. Key inputs are level of solids loading in the slurry, slurry temperature, slurry flow rate (or batch size), crystal PSD. In filtration, the membrane pore size must be chosen to retain the required PSD. Filtration pressure will affect the filtration rate and the level of moisture in the cake; it may also cause the filter cake to compress. Beware of excessive pressure as this can cause particle breakage: analysis of the filter cake properties is needed here. A challenge here is finding the balance between filtration time and final moisture content. This can only be determined in conjunction with the performance of the drying step. Lower moisture content after filtration reduces the residence time for the drying step. This can be minimized by blowing the cake with nitrogen at low pressure (0.5 bar) after filtration to assist unbound moisture removal from the cake. The designer must find the balance between these to minimize overall step time. The design variables for drying operation are shown in Fig. 9. Temperature in the drying step is critical. The melting point of the API crystal must be avoided, as well
5 Type of unit operation
SlurrySolids loading and PSD
Slurry temperature
LoD
Filter cake properties
Filtration pressure
FIG. 8 Design variables for filtration.
Filter cake LoD
API melting and annealing point
LoD
Drying time
FIG. 9 Design variables for drying.
Solvent vapourliquid properties
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms as annealing temperatures that would result in the crystal form changing. If need be, vacuum should be used during drying to reduce the boiling temperature of the solvent. Drying will generally be agitated to assist with mass and heat transfer and reduce drying time. Here again there is a delicate balance: too much agitation can lead to agglomeration and attrition in the dryer, while insufficient agitation can lead to inefficient mixing and wet pockets in the cake bed.
5.2.3 Screening and size reduction It is possible that the PSD is no longer optimal due to breakage or agglomeration during filtration and drying. Therefore, it will be necessary to break up oversized particles and remove undersized ones through milling and screening. Milling serves three functions in the process: • • •
Reducing particle size Homogenizing particle size, i.e., reducing the range of particle sizes present Breaking up of agglomerates/lumps
Milling reduces particle size by applying impact to the particles, either via mechanical means or through fluidization. There is a wide range of milling equipment available within these two categories: it is for the designer to determine which is most appropriate for a particular application. The main driver for PSD as a result of milling is residence time in the mill. Thus in a mill of fixed capacity, the feed rate of material into the mill will govern the residence time within the mill and the resulting PSD of the milled material. PAT techniques can be used to monitor the extent of size reduction in the powder to avoid overmilling the material. In some cases, flowability problems will require that the API is blended with a glidant before milling to ensure that it will flow smoothly through the mill. This will require an additional blending operation ahead of the mill. Having reduced the size of oversized particles by milling, screening can now be used to remove undersized particles. This operation is not unlike filtration in that a screen is used to allow particles below a certain size to pass through while larger particles are retained. The cut-off size for the screen will be decided by the desired pharmacological performance of the drug. Typically, screening equipment uses vibration to encourage the fine particles to drop through the screen while the coarse particles are retained. Care must be taken to avoid excessive vibration levels that might fracture the larger particles. This limit must be established during product development and testing. Screening is an absolute procedure: particles either pass through the screen or do not. The process will need to be monitored so that it can be stopped when all fines have been removed from the feed. The fine particles can be recycled, either as a seed for crystallization, or dissolved for recrystallization.
5 Type of unit operation
5.2.4 Blending Blending is the stage where the API and excipients are mixed together to create the material for tabletting. The primary goal for this process is to ensure a homogenous blend of the API and all excipients. Depending on the API properties and the properties required for tabletting, several excipients may be used. It is important that not only is the API evenly distributed throughout the blend, but that each excipient is also evenly distributed. Blending can be done one excipient at a time or with all excipients in one operation. The choice will be based on the nature of the excipients used and their proportions. As noted earlier, blending may be needed at multiple stages in the process, depending on the requirements of various steps. Each blending stage should be developed and optimized to suit the required properties of the blend. As blending is a mechanical process, it has potential to damage the material if overdone. Therefore, monitoring the progress of the blending operation is crucial. Near-infrared (NIR) spectroscopy is capable of monitoring blend uniformity and can be used as a control measure.
5.2.5 Tabletting process Tablet formation can be thought of as the process whereby the API is brought together with appropriate excipients and formed into the tablet. Regardless of the specifics of the process and formulation, it involves the following steps: • •
Milling of API and excipients Blending of API and excipients
Both of these operations have already been discussed. From here (as indicated in Fig. 5), there are three options for forming a tablet: • • •
Direct compression Dry granulation Wet granulation
These processes are already discussed in detail elsewhere in the chapter: this section will again consider some engineering aspects of the process and unit operations. Typically, tablet presses are commercially available pieces of equipment, complete with powder feed mechanisms and a press for the tablet. The only customization will be the die for the tablet itself. The engineer’s role here is first to select a suitable press from the manufacturers’ catalogues according to the requirements for the process. Table 6 lists appropriate granulation techniques for various API characteristics, for cases where the API is not suitable for direct compression. This provides a starting point for the engineer looking to design the tabletting process. A design of experiments approach can be taken to determine the relationship between key API and excipient powder characteristics, process characteristics, and desirable product attributes.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms Key API/excipient characteristics would include: • • • • •
PSD LoD Compressibility Flowability Adherence (to tablet die) Key product (tablet) attributes would include:
• • • • • •
Hardness Friability Disintegration behavior Dissolution Mass Blend uniformity
Starting with a set of excipients that are likely to give the required behavior, the DoE approach will minimize the number of experiments needed to refine the formulation. The formulation will be optimized for the equipment being used as well as the pharmacological profile desired. It is important that laboratory-scale tablet presses should mimic as closely as possible the behavior of the process-scale presses that will be used to minimize any potential error when scaling up. If this is not possible, additional testing will be needed to ensure that the formulation will work well in production equipment. When tabletting does not work, or when pharmacological performance makes it more desirable, capsule manufacture is an alternative. The main step in capsule manufacture is preparation of the powder whether it is direct fill of crystalline API, or by granulation of an API/excipient blend. Development of the process follows the guidelines already given for granulation in the previous section. As a final step, tablets may be coated. Section 3 discusses the rationale for coating of tablets and general principles involved in developing a coating formulation. Coating equipment is available off the shelf, and engineering effort is limited to ensuring that the particular coating formulation is applied evenly to the tablet/ capsule.
6 BATCH VERSUS CONTINUOUS PROCESSING Traditionally, pharmaceutical products have been manufactured in batch processes; discrete volumes of product are manufactured in individual lots, each requiring (typically) offline testing, quality control and release, resulting in long market lead times, limited ability to respond to market demands and fluctuations in product characteristics from batch to batch. Batch processing lends itself well to
6 Batch versus continuous processing
the stringent quality requirements of pharmaceutical manufacturing, in that individual lots of material can be sampled, tested, and released as product. The design and operation of a batch process are simplified relative to their continuous alternative, batch processing equipment is suited to multipurpose and multiproduct use, and the current infrastructure in pharmaceutical manufacturing environments is predominantly batch equipment. However, there are limitations associated with batch manufacturing. Batch equipment trains are capital and space intensive, can only access a limited range of processing conditions, require onerous scale-up processes to move from development to manufacturing scales, and tend to generate higher inventories of hazardous materials. The alternative to batch manufacturing is continuous manufacturing, which is based on the idea of constant flow into and out of unit operations, so that the process occurs as a function of time and flow rate. The last ten years have seen a shift toward continuous manufacturing of pharmaceuticals, due to a number of key advantages relative to traditional batch manufacturing: • •
•
• •
• •
•
Smaller equipment footprint, lower capital cost Reduced operating cost due to higher yields and fewer process steps. One study calculated up to 40% reduction in costs on moving to continuous manufacturing relative to the batch process (Schaber et al., 2011) Consistent physical properties in final product throughout manufacturing campaign—no batch-to-batch variations as products are produced at steady state, avoiding product failures. Elimination of scale up; replaced by the scale-out concept—increase number of units to increase operating volumes Transformation of the Technical Transfer of processes from Research to Manufacturing for new products—use continuous skids in Research and transfer the same skids for use in Manufacturing Online testing and quality control leading to a decrease in rejected batches or reworks—ultimately eliminating product failures Flexibility—ability to manufacture as desired with significantly reduced start-up times, reduced inventory, and reduced interproduct cleaning (through use of dedicated equipment). Conducive to the “Factories of the Future” concept—use of plug-and-produce facilities to provide for flexible customized processing streams.
There is also a regulatory driver for the Pharmaceutical Industry to move to continuous manufacturing mode: The US Food and Drug Authority (FDA) are pushing it. Janet Woodcock of the FDA delivered a presentation at the 2011 AAPS conference, which stated “Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing” (Woodcock, 2011).
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms Some progress has been realized to date. In 2015, Vertex became the first company to receive FDA approval for a drug product manufactured using continuous processing. Orkambi, a medicine for cystic fibrous, is manufactured in a continuous drug product line involving continuous mixing of API with excipients, tablet compression, and tablet finishing. Central to the concept of continuous manufacturing is process control, which becomes more challenging when process materials are in continuous motion. It becomes necessary to detect any diversion from steady state in real time and address the issue quickly to avoid the production of out of specification material. PAT has been employed to achieve greater control of continuous manufacturing processes though online/inline process monitoring.
7 PROCESS ANALYTICAL TECHNOLOGY PAT is defined as a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. PAT consists of the hardware, which takes a measurement along with the software system that completes the analysis and records the data. PAT can range from simple devices, such as an inline pH meter, to more complex instruments for inline analysis with Infrared or Raman spectroscopy. It is worth defining the terminology of measurement types: • • • •
At line: Measurement where the sample is removed, isolated from, and analyzed in close proximity to the process stream Online: Measurements where the sample is diverted from the manufacturing process and may be returned to the process stream Inline: Measurements where the sample is not removed from the process stream and can be invasive/noninvasive Offline: Measurement where the sample is removed from the process and analyzed in a laboratory setting
The implementation of PAT typically involves the insertion of a probe into the process, for example a reaction vessel, or the passage of process material across a flat probe face, for example granulated product exiting through a product chute. The probe records a signal and transmits this back to a detector, where it is converted to a process measurement. Fast consecutive measurements, in the order of seconds, are possible with certain PAT, providing process insights and understanding, which may be missed with traditional offline sampling. PAT provides the opportunity to build quality into the process, rather than test quality after the process has completed. A number of examples of popular commercially available PAT are included in Table 7, but this is not an exhaustive list.
Table 7 List of popular commercially available PAT tools for pharmaceutical development Technology
Application
Focused Beam Reflectance Measurement, FBRM
Measurement of chord length distribution of solid particles in solution, indicative of particle size
ReactIR
In-Process FTIR
Particle View P19
Probe-based video microscope that visualizes particles and particle mechanisms
Image
Supplier Mettler Toledo; www.mt.com
Lab Scale
45P GP; Process Scale
Continued
Table 7 List of popular commercially available PAT tools for pharmaceutical development—cont’d Technology
Application
Eyecon
Inline/At-line/Laboratory measurements of particle size and shape for bulk powder samples
MultiEye
Multipoint (4) Near-Infrared (NIR) spectrometer designed for both inline real-time and at-line process monitoring of bulk powder samples
Insitec
Particle size, available for dry, spray, or wet analysis
Image
Supplier Innopharma labs; www. innopharmalabs. com
Malvern; www. malvern.com
References
8 CONCLUSIONS Oral solid dosage medicines remain the most widely used medicinal forms. The development of an oral solid dosage drug begins with the physicochemical properties of the API molecule, involves rigorous preformulation assessments to characterize the needs of the API, requires selection of appropriate processing routes to handle and deliver the required specification, and continues to evolve with technology and analytical advances. An insight into each aspect of oral solid dosage development has been presented here to assist the reader in understanding the complexities and challenges involved in producing these valuable medicinal forms.
REFERENCES Almaya, A., 2009. Formulation and analytical development for low-dose oral drug products (Chapter 5). In: Zheng, J. (Ed.), Development of Low-Dose Solid Oral Formulations Using Wet Granulation. John Wiley & Sons, New Jersey. Ando, H.Y., Radebaugh, G.W., 2005. Property-based drug design and preformulation (Chapter 38). In: Hendrickson, R. (Ed.), Remington: The Science and Practice of Pharmacy, tewenty-first ed. Lippincott Williams & Wilkins, Philadelphia, pp. 720–744. Bartolomei, M., Bertocchi, P., Antoniella, E., Rodomonte, A., et al., 2006. Physico-chemical characterisation and intrinsic dissolution studies of a new hydrate form of diclofenac sodium: comparison with anhydrous form. J. Pharm. Biomed. Anal. 40 (5), 1105–1113. Bastin, R.J., Bowker, M.J., Slater, B.J., 2000. Salt selection and optimisation procedures for pharmaceutical new chemical entities. Org. Process. Res. Dev. 4, 427–435. Bele, M.H., Derle, D.V., 2012. Effect of sorbed water on disintegrant performance of four brands of Polacrilin Potassium NF. AAPS PharmSciTech 13 (1), 24–34. Bharate, S.S., Bharate, S.B., Bajaj, A.N., et al., 2010. Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J. Excipients Food Chem. 1, 3–26. Brittain, H.G., 2009. Solid-State phase transformations. In: Brittain, H.G. (Ed.), olymorphism in Pharmaceutical Solids, second ed. Informa Press, New York, pp. 481–509 (Chapter 13). Budura, E.A., Lupuleasa, D., Arama˘, C., Nit¸ulescu, M., Balaci, T., et al., 2011. Preparation and characterization of inclusion complexes formed between simvastatin and hydroxypropylβ-cyclodextrin. Farmacia 59 (4), 512–530. Carstensen, J.T., 2000. Preformulation (Chapter 9). In: Carstensen, J.T., Rhodes, C.T. (Eds.), Drug Stability, third ed. Marcel Dekker, New York, pp. 237–260. Carstensen, J.T., 2002. Preformulation (Chapter 7). In: Banker, G.S., Rhodes, C.T. (Eds.), Modern Pharmaceutics, fourth ed. Marcel Dekker, New York, pp. 167–185. Chen, X.-Q., Antman, M.D., Gesenberg, C., et al., 2006. Discovery pharmaceutics— challenges and opportunities. AAPS J. 8, E402–E808. Di, L., Kerns, E., 2003. Profiling drug-like properties in discovery research. Curr. Opin. Chem. Biol. 7, 402–408. Gibson, M., 2009. Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. CRC Press, New York. Gokhale, R., Sun, Y., Shukla, A.J., et al., 2005. High-shear granulation (Chapter 7). In: Parikh, D.M. (Ed.), Handbook of Pharmaceutical Granulation Technology. Taylor & Francis Group, Boca Raton, FL, pp. 191–228.
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CHAPTER 2 The development of a pharmaceutical oral solid dosage forms Grekas, N., 2005. Organic Impurities in Chemical Drug Substances. Pharmaceutical Technology, Europe. Guy, R., 2000. International conference on harmonization impurity guidelines—the industry perspective. Drug Inf. J. 34, 903–907. Hancock, B.C., Colvin, J.T., Mullarney, M.P., Zinchuk, A.V., et al., 2003. Pharmaceutical powders, blends, dry granulations, and immediate-release tablets. Pharm. Technol., 64–80. Hickey, A.J., Smyth, H.D.C., 2011. A practical guide to equipment selection and operating techniques. In: Hickey, A.J., HDC, S. (Eds.), Pharmacocomplexity, outlines in pharmaceutical sciences. American Association of Pharmaceutical Scientists, Texas. Holm, P., 1997. High shear mixer granulators. In: Parikh, D. (Ed.), Handbook of Pharmaceutical Granulation Technology. Marcel Dekker, New York. Impurities in New Drug Substances, ICH Guidelines (Q3A). Liberman, H.A., Lachman, L., Schwart, J.B., 1989. Pharmaceutical Dosage Forms—Tablets, second ed. vol. I. Informa Healthcare, 88–120 (Tablet excipients). Lieberman, H.A., Lachman, L., Schwartz, J.B. (Eds.), 1989. Pharmaceutical Dosage Forms: Tablets. In: vol. 1. Marcel Dekker INC, New York. Malkowska, S., Khan, K.A., 1983. Effect of recompression on the properties of tablets prepared by dry granulation. Drug Dev. Ind. Pharm. 9 (3), 331–347. Morin, G., Briens, L., 2013. The effect of lubricants on powder flowability for pharmaceutical application. AAPS PharmSciTech (3), 1158–1168. Mortko, C.J., Sheth, A.R., Variankaval, N., Li, L., Farrer, B.T., et al., 2010. Risk assessment and physicochemical characterization of a metastable dehydrate API phase for intravenous formulation development. J. Pharm. Sci. 99 (12), 4973–4981. Niazi, S.K. (Ed.), 2009. Handbook of Pharmaceutical Manufacturing Formulations. In: vol. 3. Informa Healthcare, New York. Parikh, D.M. (Ed.), 2005. Handbook of Pharmaceutical Granulation Technology. Taylor & Francis Group, Boca Raton, FL. Parikh, D.M., Mogavero, M., 2005. Fluidized bed granulation (Chapter 9). In: Parikh, D.M. (Ed.), Handbook of Pharmaceutical Granulation Technology. Taylor & Francis Group, Boca Raton, FL, pp. 247–310. Prescott, J.A., Barnam, R.A., 2010. On powder flowability. Pharm. Technol. 24, 60–84 RaoNageswara, R., Nagaraju, V., 2003. An overview of the recent trends in development of HPLC methods for determination of impurities in drugs. J. Pharm. Biomed. Anal. 33, 335–377. Rolf, H. (Ed.), 2006. Polymorphism: In the Pharmaceutical Industry. Wiley, Basel Switzerland. Rus, L.M., Tomuta, I., Iuga, C., Maier, I., Kacso, G., Borodi, I., Bratu, M., Bojita, et al., 2012. Compatibility studies of indapamide/pharmaceutical excipients used in tablet preformulation. Farmacia 60 (1), 92–101. Satoskar, R.S., Rege, N., Bhandarkar, S.D. (Eds.), 2015. Pharmacology and Pharmacotherapeutics. Popular Prakashan, Mumbai, pp. 1–79. Schaber, S.D., Gerogiorgis, D.I., Ramachandran, R., Evans, J.M.B., Barton, P.I., Trout, B.L., et al., 2011. Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Ind. Eng. Chem. Res. 50, 10083–10092. Shangraw, R.F., Lieberman, H.A., Lachman, L., Schwartz, J.B. (Eds.), 1989. Compressed tablets by direct compression (Chapter 4). In: Pharmaceutical Dosage Forms: Tablets. vol. 1. Marcel Dekker INC, New York, pp. 195–246. Tapper, G., Lindberg, N.O., 1986. The granulation of some lactose qualities with different particle size distributions in a domestic-type mixer. Acta Pharm. Suec. 23, 47–56.
References
The British Pharmacopoeia, Her Majesty’s Stationery Office, London, 2010. Verbeek, R., Kanfer, I., Walker, R., 2006. Generic substitution: the use of medicinal products containing different salts and implications for safety and efficacy. Eur. J. Pharm. Sci. 28, 1–6. Winfield, A.J., Richards, R.M.E., 2004. Pharmaceutical Practice, third ed. Churchill livingstone, Sydney Torento, pp. 247–263. Wischke, C., Zhang, Y., Mittal, S., Schwendeman, S.P., 2010. Development of PLGA-based injectable delivery systems for hydrophobic fenretinide. Pharm. Res. 27 (10), 2063–2074. Woodcock, J., 2011. In: Oral presentation, American Association of Pharmaceutical Sciences Annual Meeting, Washington DC. Yang, Y., Engkvist, O., Llinas, A., et al., 2012. Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds. J. Med. Chem. 55, 3667–3677. Yu, L.X., Carlin, A.S., Amidon, G.L., Hussain, A.S., et al., 2004. Feasibility studies of utilizing disk intrinsic dissolution rate to classify drugs. Int. J. Pharm. 270, 221–227. Yu, L.X., et al., 2014. Understanding pharmaceutical quality by design. AAPS J. 16, 771–783.
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