Co amorphous systems: A product development perspective

Accepted Manuscript Title: Co Amorphous Systems: A Product Development Perspective Author: Rahul B Chavan Rajesh Thipparaboina Dinesh Kumar Nalini R Shastri PII: DOI: Reference:

S0378-5173(16)31008-0 http://dx.doi.org/doi:10.1016/j.ijpharm.2016.10.043 IJP 16174

To appear in:

International Journal of Pharmaceutics

Received date: Revised date: Accepted date:

24-9-2016 18-10-2016 19-10-2016

Please cite this article as: Chavan, Rahul Kumar, Dinesh, Shastri, Nalini R, Co Product Development Perspective.International http://dx.doi.org/10.1016/j.ijpharm.2016.10.043

B, Thipparaboina, Rajesh, Amorphous Systems: A Journal of Pharmaceutics

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Co Amorphous Systems: A Product Development Perspective

Rahul B Chavana, Rajesh Thipparaboinaa, Dinesh Kumara,b, Nalini R Shastria*

a

Solid State Pharmaceutical Research Group (SSPRG), Department of Pharmaceutics, National

Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India b

Solid State Pharmaceutical Cluster (SSPC), School of Pharmacy and Pharmaceutical Sciences,

Trinity College Dublin, The University of Dublin, Ireland

*Corresponding author. Nalini R Shastri Tel. +91-040-23423749 Fax. +91-040-23073751 E-mail: [email protected], [email protected] Address: Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Balanagar, Hyderabad, India, Pin code – 500037

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Graphical abstract

Abstract Solubility is one of the major problems associated with most of the new chemical entities that can be reasonably addressed by drug amorphization. However, being a high-energy form, it usually tends to re-crystallize, necessitating new formulation strategies to stabilize amorphous drugs. Polymeric amorphous solid dispersion (PASD) is one of the widely investigated strategies to stabilize amorphous drug, with major limitations like limited polymer solubility and hygroscopicity. Co amorphous system (CAM), a new entrant in amorphous arena is a promising alternative to PASD. CAMs are multi component single phase amorphous solid systems made up of two or more small molecules that may be a combination of drugs or drug and excipients. Excipients explored for CAM preparation include amino acids, carboxylic acids, nicotinamide and saccharine. Advantages offered by CAM include improved aqueous solubility and physical stability of amorphous drug, with a potential to improve therapeutic efficacy. This review attempts to address different aspects in the development of CAM as drug products. Criterion for co-former selection, various methods involved in CAM preparation, characterization tools, stability, scale up and regulatory requirements for the CAM product development are discussed.

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Keywords: Co amorphous system, amorphous solid dispersion, polymers, miscibility, phase separation, stability

1.

Introduction

Poor physicochemical properties such as low solubility and permeability, pose challenges during the transition of promising new chemical entities (NCE) into a successful drug. Low solubility is accompanied by slow dissolution and poor bioavailability. Hence, great deal of effort is required to improve solubility, dissolution and ultimately bioavailability. Conversion of crystalline drug to an amorphous form offers increased apparent solubility and dissolution, often leads to an increase in bioavailability (Hancock and Zografi, 1997; Kaushal et al., 2004). An amorphous solid (glass), unlike a crystalline solid, may have short-range molecular order, with no longrange order of molecular packing or well-defined molecular conformation (Yu, 2001). Presence of high internal energy and enhanced molecular mobility in amorphous materials leads to higher reactivity, consequently resulting in thermodynamic instability as compared to their crystalline counterparts. In contrast, often the true solubility advantage of these high-energy forms is lost due to stability concerns, owing to the tendency of amorphous systems to reorganize into ordered crystal lattice, by a process of recrystallization or devitrification (Kaushal et al., 2004). Polymeric amorphous solid dispersion (PASD) has been a preferred method to achieve the primary advantage offered by an amorphous form to increase apparent solubility. In PASD, the molecules are kinetically entrapped between the polymer chains in a high energy non-crystalline state leading to improved stability, as compared to pure amorphous drug (Chiou and Riegelman, 1971; Qian et al., 2010; Rumondor et al., 2009a). Extensive literature is available on the mechanisms of molecular dispersion or glass solution of the drug in a glassy polymer matrix. 3

Interested readers are encouraged to refer to the excellent reviews (Chiou and Riegelman, 1971; Hancock and Zografi, 1997; Kaushal et al., 2004). Development of PASD faces many hurdles (Figure 1), the major being the poor solubility of the drug in the polymer. This usually results in incorporation of high amount of polymer, increasing final dosage form volume, thus limiting their use, especially for high dose drugs. In addition, hygroscopic nature of few polymers, phase transformation of amorphous drug during processing or storage, scale up and processing difficulties in conversion of PASD into dosage forms, create hurdles in the path of final dosage form development (Kaushal et al., 2004). These challenges usually negate the solubility and dissolution advantage of amorphous systems (Figure 1), occasionally making the product unsafe and inefficacious, as seen by the recall of many PASD products by the FDA (Guo et al., 2013). Past few years has seen rapid growth of binary amorphous systems known as co amorphous systems (CAM) incorporating drug with small molecules instead polymers (Dengale et al., 2016). This approach has established itself as a promising alternative to PASD, especially in the form of drug-drug CAM (Table 1) which can be administered as combination therapeutics (Dengale et al., 2014; Suresh et al., 2014). In addition to drug-drug CAM, combination of drugs with low molecular weight excipients such as amino acids, saccharine etc have also reported potential benefits (Ali et al., 2015; Gao et al., 2013; Jensen et al., 2015). These systems have reported enhanced solubility, dissolution rate and physical stability of amorphous form of drug. In the current scenario, huge growth rate of CAM can be forecasted especially in drug-drug systems, hence drawing attention of both academia and industry. Recently, Dengale et al., has provided an excellent overview of CAM, describing dissolution enhancements and stability advantages offered by these systems (Dengale et al., 2016). However, the current literature is lacking in important aspects of product development such as stability, scale up and regulatory 4

requirement for approval. The objective of manuscript is to provide a formulation perspective on CAM and review different aspects in the development of CAM as a drug product. Various aspects like criterion for co-former selection, methods involved in CAM preparation, characterization, scale up and regulatory aspects for approval of the final dosage form are discussed. A protocol for screening and development of CAM based drug products is also proposed. 2.

History of co amorphous system and its classification

Amorphous systems using small molecules like urea, citric acid, tartaric acid as amorphous stabilizers have been reported since long (Ford and Rubinstein, 1981; Liu et al., 2004; McGinity et al., 1984). However, the term “co amorphous” was coined by Chieng et al, in 2009 (Chieng et al., 2009). This term was introduced to differentiate amorphous mixture containing two small molecules from the term PASD. CAM is defined as “a multi-component single phase amorphous solid system which lacks periodicity in lattice and is associated by weak and discrete intermolecular interactions between the components” (Suresh et al., 2014). They possess shortrange interactions such as hydrogen bonding of carboxylic acids, phenols/alcohols and carboxamides similar to amorphous system of single component systems. However, this system differs from cocrystal, salt or eutectic primarily by its amorphous nature which is characterized by presence of broad hump (‘amorphous halo’) in the X-ray diffractogram (Grohganz et al., 2013). Yamamura et al, developed the first drug-drug CAM by combining cimetidine with naproxen, (Yamamura et al., 2000; Yamamura et al., 1996) claiming improvement in solubility and dissolution rate due to stabilization of amorphous form of both drugs through intermolecular hydrogen bonding. Expanding this potential, Lu et al, reported the use of small molecule excipients like citric acid for stabilization of amorphous form of indomethacin (Lu and Zografi, 5

1998). Stabilization of the amorphous drug was accomplished by increasing Tg of the mixture via salt formation or intermolecular interactions. Other small molecules like sugars, amino acids, nicotinamide, urea, carboxylic acids have also been explored (Lu and Zografi, 1998; Serajuddin, 1999). In the following sections, we have classified small molecules based CAM as drug-drug and drug-excipient combinations. 2.1 Drug-drug CAM Drug-drug CAM is a binary amorphous system in which one of the drug act as an amorphous stabilizer. Several drug-drug CAMs were reported in last few years (Table 1). Apart from the advantage of stabilization, solubility and dissolution, they offer a platform for the development of new combinational therapy. Combination of drugs from two different therapeutic categories helps in more efficient therapy. Generally CAM are produced in molar ratio of 1:1, which may show improvement in stability as it is assumed that both components of CAM interact at molecular level through hydrogen bonds (Alleso et al., 2009; Lobmann et al., 2011; Suresh et al., 2014). In addition to the potential therapeutic advantage, co amorphous approach offers bioavailability enhancement as one of the drugs may act as dissolution-enhancing and amorphous-stabilizing agent for the second drug (Dengale et al., 2014). The first drug-drug CAM was reported by Yamamura et al, in 1996. They prepared it by combining cimetidine with naproxen, (Yamamura et al., 1996) indomethacin (Yamamura et al., 2000) and diflunisal (Yamamura et al., 2002) by solvent evaporation method. To date, less than 20 drug-drug CAMs (Table 1) are reported, probably due to limited availability of pharmacologically relevant drug pairs with glass forming ability that can be used in combination therapy. 2.2

Drug- excipient CAM

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Drug-excipient CAM can improve dissolution and stability through various mechanisms ranging from intermolecular interactions such as hydrogen bonding, charge assisted interactions etc, to improvement in miscibility of components. Since long, urea and sugars have been used for stabilization of amorphous drug (Descamps et al., 2007; Liu et al., 2004). Many sugar molecules like lactose, trehalose, and mannitol have proven their potential in amorphous stabilization (Descamps et al., 2007). Cocrystal co-formers such as saccharine and nicotinamide for CAM preparation were explored by Gao et al, (Gao et al., 2013) and Shayanfar A et al, (Shayanfar et al., 2013) respectively. Amino acid and carboxylic acids have also demonstrated their utility for the formation of CAM. Among these co-formers, amino acids are extensively used for CAM preparation. CAMs reported in literature to date and list of patents granted under CAM are depicted in table 1 table 2 respectively.

3.

Development of co amorphous system

The surge of interest in this multi component system during the last decade is being driven by their potential utility as an alternative to PASD with improved physicochemical properties. However, development of CAM is not simple as the selection of appropriate co-former is a tedious process and requires systematic investigation of crystallization tendency of co-former. Similarly, other aspects like manufacturing and stability also needs careful consideration before the process of transformation of CAM to a suitable dosage form is complete. 3.1 Co-former selection In the development of CAM, selection of co-former is a crucial step as it decides the fate of the final product in terms of stability and pharmaceutical performance (Korhonen et al., 2016). Co-

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former can be a potential drug molecule or a low molecular weight excipient. Major challenge for designing drug-drug CAM lies in selection of drug candidates which can form glassy system with each other. This process can be assisted by the use of quantum mechanics for assigning various molecular interactions in FTIR and Raman spectra and providing insights into the near range order of amorphous systems (Korhonen et al., 2016) to confirm the formation of co amorphous mixture through molecular interactions. Lobmann K et al, investigated the formation of heterodimer in indomethacin and naproxen CAM system by using quantum mechanics (Lobmann et al., 2013b). Russo M. G. et al, further explored the use of quantum mechanics in evaluating intermolecular interactions between drug and co-former of CAM by studying the hydrogen bonding interactions between omeprazole and amoxicillin. They performed density functional theory calculations (DFT) followed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis in order to find out the formation of heterodimer at the molecular level, which were supported by spectroscopic experimental findings (Russo et al., 2016). However, such combination might not provide any therapeutic benefits until supporting evidence of practical application in therapy or synergism or drug-drug interactions is not provided. Most of the studies reported for drug-drug CAM were more focused towards the stabilization of amorphous form of drug, identification of mechanism for stabilization and improving the biopharmaceutical properties of drugs. Little information is available regarding therapeutic benefits of CAM, which requires detailed clinical investigation. Limitations for the development of drug-drug CAM paved path for the use of low molecular weight excipients like amino acids, sugars, saccharine, nicotinamide and citric acid. Descamps et al, prepared co milled mixtures of lactose with mannitol and budesonide using ball mill. The later achieved molecular level mixing at all molar fractions of budesonide studied and was 8

characterized by a single Tg of the mixture (Descamps et al., 2007). Selection of appropriate drug-excipient system capable of forming intermolecular interactions is the first step towards formation of stable CAM (Jensen et al., 2014; Lenz et al., 2015). Qian Shuai et al, prepared a co amorphous mixture of lurasidone hydrochloride with saccharine. Charge assisted hydrogen bonding between N+-H group of lurasidone hydrochloride and C=O group of saccharine resulted in enhanced physical stability as compared to pure amorphous lurasidone hydrochloride, in addition to solubility and dissolution enhancement. Along with intermolecular interactions, miscibility is another parameter which is prominent for amorphous stabilization (Qian et al., 2015). Lu et al, showed the potential of citric acid in the formation of a miscible system with indomethacin. Miscibility of both components was observed up to 0.25 weight fraction of citric acid, which was indicated by a single Tg of the mixture. This miscibility was a result of hydrogen bonding between carboxylic acid and hydroxyl groups of the individual components (Lu and Zografi, 1998). Amino acids are an essential component of drugs receptors, selection of those amino acids should hence be a promising lead for CAM development because at the active site of receptor, amino acids interact with the drug at a molecular level (Lobmann et al., 2013a). Use of amino acid for stabilization of amorphous drug was introduced by Lobmann et al, who developed CAM in which receptor amino acids relevant for a drug were chosen for stabilization purpose (Lobmann et al., 2013c). Ball milling was used for preparation of CAM of carbamazepine and indomethacin in combination with corresponding receptor amino acids, phenyl alanine: tryptophan and arginine: tyrosine, respectively. In case of indomethacin, tyrosine and arginine amino acids were part of receptor where indomethacin binds (Rowlinson et al., 2003). FTIR investigations revealed specific peak shifts in the vibrational modes of functional groups of drug 9

and amino acid which were indicative of formation of specific intermolecular interactions of drug with amino acids. This hindered drug-drug intermolecular interactions, ultimately delaying re-crystallization. Similar approach was applied for carbamazepine where in phenyl alanine and tryptophan amino acids which are part of Na+ channel were used for the preparation of CAM (Yang et al., 2010). This approach was also explored for stabilization of amorphous form of naproxen (Jensen et al., 2014), indomethacin and furosemide (Lenz et al., 2015) (Table 1). Later on it was demonstrated that the presence of a receptor amino acid was not mandatory for the formation of CAM (Lobmann et al., 2013a; Lobmann et al., 2013b). This was further justified by the fact that the conditions and interactions in vivo and in solid state differ significantly i.e. whole amino acid interacts with the drug in solid state, but in vivo at the target site, amino acids are not able to react with drug, as carboxylic acid and amine head groups are involved in the peptide backbone of the receptor (Lobmann et al., 2014; Lobmann et al., 2013b). Laitinen R et al, found that non-receptor amino acid; threonine enhances amorphous form stabilization and dissolution of glibenclamide, equivalent to receptor amino acid (Laitinen et al., 2014a). Selection criterion for co-former is not extensively explored. Recently Ueda et al, emphasized the importance of physicochemical properties of co-former like crystallization tendency, molecular flexibility and Tg in formation and stabilization of CAM. Multivariate (partial least squares discriminative analysis, PLS-DA) analysis was used to evaluate the contribution of physicochemical factors in the formation of co amorphous mixtures. It was observed that several properties like glass forming ability, area/volume and flexibility (i.e. molecular weight, Kier flex and rotatable bond number), reduced glass transition temperature (Trg = Tg/Tm), hydrogen bonding acceptor number (interestingly not the donor number), topological polar surface area and polarizability contributed significantly to the inhibition of the recrystallization of amorphous 10

naproxen (Ueda et al., 2016b). Gniado K et al, demonstrated the impact of three co-formers (deoxycholic acid, citric acid and sodium taurocholate) on dissolution rate of sulfamerazine CAM. Even though all co-formers stabilize the amorphous state of drug during storage, only sodium taurocholate provided dissolution advantage. This was attributed to extensive gelation of drug with deoxycholic acid which hindered drug release in dissolution medium, whereas poor dispersability was responsible for poor dissolution with citric acid (Gniado et al., 2016). From the above discussion, it is understandable that the process of screening of co-former is complex. Hence there is need of computational methods or theoretical approaches to solve this problem to save time and resources. Few studies demonstrated applicability of theoretical approaches in screening of co-formers identifying miscibility in amorphous state as a primary requirement. Flory-Huggins interaction parameter (χ) (Pajula et al., 2014) and solubility parameter (δ) (Jensen et al., 2016a; Lobmann et al., 2013c) are used to predict the miscibility of components. Two substances can be considered miscible with each other if the difference in their solubility parameters (Δδ) is smaller than 7.0 MPa (Greenhalgh et al., 1999). However, common approach which features systemic use of computational strategies for screening of suitable coformer in the development of commercially feasible CAM is way behind and needs exploration. 3.2 Preparation methods Numerous lab scale methods are reported for preparation of amorphous systems. These preparation methods can be categorized into thermal method (melt quenching), solvent evaporation method and milling method (Figure 2). Recently, Lim W et al, compared ball milling, co evaporation and quench cooling for preparation of indomethacin: cimetidine and naproxen: cimetidine CAM. They concluded that preparation methods were found to be responsible for structural characteristics of final product, thus highlighting the importance of 11

preparation methods and process variables (Lim et al., 2016). Therefore, selection of appropriate preparation method is crucial to ensure the quality and stability of final product. Various properties of drug and excipients like thermal stability, melting point and crystallization tendency influence the selection of preparation method. Quench cooling is a well-known technique for the production of small quantities of amorphous phase for evaluation purpose from thermostable drugs. Its applicability was demonstrated in case of naproxen: indomethacin CAM (Lobmann et al., 2013b). Both these drug molecules are thermally stable and their amorphization tendency is very poor. Amorphous form of naproxen prepared by milling methods i.e. vibrational ball milling, cryo-milling was found to be unstable and recrystallized rapidly in comparison to quench cooled CAM. Milling methods like ball milling and cryo milling have demonstrated their potential in generation of stable CAM and are most widely used methods due to ease of handling. Final product properties depend upon the milling temperature and thermal stability of the drug along with its Tg. Benefits of ball milling include low chemical degradation and high recovery compared to other preparation methods (Jensen et al., 2014). Efficiency of the process increases if the milling temperature is below Tg of drug. This finding provides basis for cryo milling of drugs with low Tg wherein liquid nitrogen is used to reduce the processing temperature (Laitinen et al., 2014b). However, it is a laborious, time-consuming method with a high possibility of contamination due to presence of crystalline impurity. Apart from quench cooling and milling, solvent evaporation technique can be used in generation of CAM. This method was successfully employed for generation of indomethacin: arginine CAM. Solution of indomethacin and arginine at 1:1 molar ratio was spray dried to produce amorphous product (Lenz et al., 2015). Major disadvantages of solvent evaporation 12

method include selection of a common solvent for both constituents. Similarly, presence of solvent residues may create stability problem via recrystallization or solvate formation during storage. Solvent removal rate and temperature have significant effect on stability, dissolution and particle size of drug and hence needs careful evaluation. In addition, low yield and high cost of recovery of solvent poses economic limitations on this method. 3.3 Scale up Major challenge of a CAM system is its scale up and manufacturing for commercialization. Current preparation methods are for lab scale and are suitable for making few milligrams to grams of CAM products. Several factors like temperature, moisture content, solvent properties, mechanical and thermal stress during processing may contribute to recrystallization of drug from amorphous form. In addition to these factors, preparation method is also crucial for fulfilling the desired outcome i.e. stable amorphous product with improved bioavailability (Vasconcelos et al., 2016). Generally, physicochemical properties of drug and its co-former are key elements for selection of a rational and a viable manufacturing method, wherein melting point and thermal stability of the CAM components play a major role. Melting methods are utilized for screening or optimization purposes wherein scale up is not expected. Use of jacketed vessels and heat transfer coil systems may not be efficient in scale up of molten method due to the risk of non homogeneity of the final product wherein presence of even a small fraction of unreacted components may hamper the performance of the product. In addition to these issues, in-line degradation and uneven mixing limits the use of melt methods for CAM preparation (Qi et al., 2014). However, newer processing techniques based on melting of components like hot melt extrusion (HME) have been used to scale up PASD products successfully with several PASDs available in market that are manufactured by HME process. It will hence be a logical 13

extrapolation to use HME for CAM preparation because of the physical similarity of the end product desired. HME offers advantages such as continuous and solvent free processing with ease of scale-up due to availability of different equipment capacities to develop and optimize at bench and pilot plant level. In addition, this method is amicable to in-line monitoring for mixing efficiency, in process degradation and to study the intermolecular interactions between drug and co-former. However, HME needs exhaustive study of various process variables and properties of components as they can significantly impact the performance of the final product (Qi et al., 2014; Vasconcelos et al., 2016). Ball milling is another alternative which has proven its scalability for single component amorphous systems. However, ball milling faces challenges like high mechanical stress and difficulty in achieving a homogeneous mix for large scale processes, coupled with charge build up and phase transformation issues. Milling temperature is a key operational parameter as the outcome of the process and product is dependent on it. Heat generated during milling affects the stability of the product. During milling, the drug tends to crystallize if the temperature of processing rises above the Tg of the drug. In addition, increased temperature increases the molecular mobility of drug which may result into phase separation (Qi et al., 2014). Milled product sticks to the wall of the milling chamber because of charge development on the particles on size reduction, which create problem in recovery of product from chamber. Similarly, these charges may aggravate the recrystallization tendency in the product. Hence, application of this method should be restricted to thermally stable drugs and co-formers with higher Tg. Among all these preparation methods, solvent evaporation by spray-drying has established its potential in the production of stable amorphous glass solutions, as its robustness during scale up of solid dispersions is well known (Qi et al., 2014). Selection of solvent is the key factor as 14

effectiveness of this method for large scale production may get compromised due to solvent loading capacity and solvent toxicity. The yield, quality and morphology of the product, and various safety issues depend on boiling point of the solvent and solubilization capacity. Many factors like thermal stability of drugs/excipients, molecular mixing, phase separation, temperature, solvent induced recrystallization, solvent toxicity, and amorphous to crystalline ratio in final product should be carefully considered while designing a scalable process by solvent evaporation. Solvent evaporation technique in addition may pose environmental challenges (Paudel et al., 2013). The output in terms of batch size, particle properties and process yield must be optimized. For instance, this technique generates porous, small and round particle with a tendency to retain some solvent, which may induce drug crystallization during processing or on storage. Besides various process parameters, configuration and dimensions of spray drying instrument must be adjusted for a technology transfer from lab scale to industrial scale so that the critical quality attributes (such as stability, improvement in dissolution, solubility and bioavailability) are not affected (Singh and Van den Mooter, 2016). Recently, few reports have emerged where CAM products were produced by spray drying (Jensen et al., 2016a) which were subsequently formulated into final dosage forms (Lenz et al., 2015). Jensen et al, have demonstrated the feasibility of spray drying for the preparation of drug-amino acid CAM formulations on a larger scale. Amorphous salt of indomethacin–arginine prepared by spray drying method exhibited comparable properties as that of the ball milled formulation (Jensen et al., 2016a). As spray drying makes co amorphous indomethacin–arginine available in a larger amount, the further successful processing to a final drug product i.e. tablet form was reported by Lenz E. et al (Lenz et al., 2015). Integration of CAM preparation methods with process

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analytical technology tool (PAT) control is required to monitor and control large scale manufacturing of CAM. 3.4 Characterization of CAM The qualitative and quantitative characterization of miscibility, phase separation, crystallinity, moisture or solvent residue, molecular interactions, molecular mobility, surface chemistry and morphology of CAM requires advanced characterization tools (Figure 3). Thermal, moisture sorption, and diffractometric tools are commonly used to understand the performance and stability of CAM. In addition, dielectric spectroscopy, isothermal microcalorimetry and thermomechanical techniques also find their application to understand the stability aspects of the amorphous system. SS-NMR (Han et al., 2016), FTIR (Qian et al., 2015), Raman, and other vibrational spectroscopic techniques (Hu et al., 2014) are mainly used for analyzing molecular interaction between components of CAM, structural changes during phase separation and for quantification of crystallinity. The use of simultaneous estimation tools for the integrated information with a spatiotemporal resolution has increased in the last few years as no single characterization technique is adequate. DSC helpful in characterizing the Tg, melting, enthalpy recovery, desolvation, degradation, crystallization, and degradation transitions of amorphous systems (Paudel et al., 2014). Modulated temperature (mDSC) resolves the problem of overlapping transitions often seen with conventional DSC. mDSC has been used for studying molecular mobility at or below T g, isothermal/ non isothermal crystallization, percentage crystallinity, melting and mixing interactions (Paudel et al., 2014). DSC is also used for determining enthalpy recovery and fragility of the amorphous material (Wang et al., 2002). Fragility index and kinetic fragility of

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quercetin which was determined by DSC, helped in concluding that quercetin is a good glass forming agent, thus assisting in development of ritonavir: quercetin CAM (Dengale et al., 2015). Halo pattern in X-ray diffractogram is a reliable indicator of amorphous nature of sample, but lacks direct information on miscibility. Alternative methods like chemometric treatment and computational analysis of PXRD data can be used to gather qualitative or semi quantitative information on miscibility of amorphous systems. Crystallization as a function of temperature, relative humidity, time, and/or pressure can be studied using PXRD due to its instrumental flexibility (Guns et al., 2011). PXRD is a well-established method for quantifying percentage crystallinity present initially or when induced during processing and storage. Apart from DSC and PXRD, numerous tools that are used for analysis of structural properties of CAM are depicted in figure 3. Details of these numerous techniques and their working principles and applicability in PASD are already available in the literature (Paudel et al., 2014) which can be easily applied to CAM for the determination of intermolecular interactions, miscibility, recrystallization tendency, relaxation behavior, anti plasticization effect of co-former and other related attributes of CAM. DVS analysis measures gravimetric moisture sorption-desorption by applying RH ramp. In gravimetric measurement of amorphous material, sorption or desorption as a function of time at a constant RH or as a function of RH is performed to provide abundant information on amorphization and recrystallization tendency. Properties that can be measured from gravimetric measurement by DVS include moisture-induced glass transition, drug–polymer interactions, hydrate formation/dehydration and crystallization (Rumondor et al., 2009b). Particulate or bulk properties like hygroscopicity, diffusivity, pore size and surface area can also be characterized using DVS (Sheokand et al., 2014). However, for quantitative determination of enthalpy relaxation of amorphous system, isothermal microcalorimetry and dielectric 17

spectroscopy are used preferentially. These complementary techniques can also be useful for non specific thermal activity monitoring of heat change during any process. Isothermal microcalorimetry can also be used in determination of crystallinity. In addition, use of spectroscopic techniques such as FTIR (Qian et al., 2015), near infra red spectroscopy (Hu et al., 2014), Raman spectroscopy, SS-NMR (Han et al., 2016) etc, for identification of molecular interactions between drug and co-former are popular. As evident by many reported studies on CAM, presence of hydrogen bonding, π-π interactions can be identified by any one of these characterization techniques. 3.5 Evaluation of pharmaceutical and biopharmaceutical properties Major motive behind preparation of CAM is the improvement of physicochemical properties of drugs which are critical for their pharmaceutical and biopharmaceutical performance. Enhancements in solubility, dissolution and stability have been demonstrated in more than 35 studies of CAM. Therapeutic advantages offered via combination of two drugs have also been investigated. Many of them have claimed improvement in physical and chemical stability via coamorphization. An excellent example is that of ritonavir and indomethacin which degrades at 40 ⁰C immediately after their conversion into amorphous form (Dengale et al., 2014). Dengale S. J. et al, prepared CAM system of ritonavir with indomethacin which showed improved chemical stability and confirmed it by absence of any extra peak in chromatograms of prepared binary amorphous systems. Physical stability of this system in three different ratios were found to exhibit superior physical stability for a maximum period of 90 days, at all tested temperatures (i.e. 4 ⁰C, 25 ⁰C, 40 ⁰C) (Dengale et al., 2014). In addition, the CAM demonstrated significant improvement in the dissolution rate as well as in the total amount of drug dissolved for amorphous ritonavir. CAM of Simvastatin: amino acid has also been developed with an objective 18

to improve the physical stability of the amorphous drug. Simvastatin is widely used for the treatment of hypercholesterolemia but its pure amorphous form crystallizes within a few days at elevated temperature (40°C/0% RH) and humidity (ambient/60% RH). CAM of simvastatin with lysine showed improved physical stability in contrast to pure amorphous simvastatin (Craye et al., 2015). Numerous studies have reported the development of CAM with an objective of enhancing dissolution rate of drugs such as nateglinide: metformin hydrochloride (Wairkar and Gaud, 2015), indomethacin: arginine (Lenz et al., 2015), lurasidone hydrochloride: saccharin (Qian et al., 2015), repaglinide: saccharin (Gao et al., 2013), indomethacin: naproxen (Lobmann et al., 2011) etc. Some have claimed significant improvement in solubility of amorphous drug when compared to their crystalline counterpart. In addition to enhancement of dissolution rate, some CAM systems enabled synchronized drug release as achieved with indomethacin: naproxen (Lobmann et al., 2011) and naproxen: cimetidine (Alleso et al., 2009). Analysis of reported pharmacokinetic results on CAM leads to a conclusion that enhanced AUC is likely due to improved solubility. Significant change in Cmax and AUC was exhibited by many CAM. Impact of different CAM drug systems on Cmax ranged from 1.3 to around 30 fold increase (Suresh et al., 2014) while AUC enhancements were in between 1 to 5 folds. Additionally, significant reduction in Tmax was also observed which can be attributed to the solubility advantage of amorphous systems. In case of drugs which are P-gp substrate, permeation of drug across GI membrane might have been compromised due to poor solubility of drug, which limits the concentration of drug penetrating into the enterocyte by preventing the saturation of efflux transporters. Since, P-gp efflux transporters are amenable to saturation, the solubility advantage provided by CAM results in higher luminal concentration of drug, probably resulting in saturation of transporters and ultimately enhancing the absorption of drug. This 19

effect can be multiplied if P-gp inhibitors as co-formers are incorporated with P-gp substrate drugs in CAM. Combination of talinolol (P-gp substrate) with naringin (P-gp inhibitor) in CAM resulted into 9 fold enhancement in AUC of talinolol as naringin inhibited P-gp efflux transporter. In situ permeability studies confirmed the effect of naringin on P-gp inhibition wherein the permeability of talinolol was increased to 3.16 × 10-5 cm/s in contrast to 2.48 × 10-5 cm/s in absence of naringin (Teja et al., 2015). Dengale S. J. et al, reported that increased permeation of ritonavir through enterocyte after oral administration of ritonavir- quercetin CAM to rats might be due to solubility advantage of CAM and not because of P-gp inhibition (Dengale et al., 2015). 3.6 Formulation Generally CAM systems are intended for oral administration, and can be formulating into tablets or capsules. Challenges like soft and tacky nature of product, difficulty in pulverization and sifting, poor flow, poor compressibility and stability of amorphous form of drug under mechanical pressure are critical for converting CAM into final dosage form. These parameters might also have implications on the stability and the dissolution behavior of the amorphous drug product. In addition, few reported CAM were formed and stabilized by means of molecular interactions such as hydrogen bonding, charge assisted interactions, etc, and hence mixing of CAM with excipients for tablet preparation may hamper the physical stability and dissolution rate of amorphous drug. Lenz E et al, demonstrated enhanced physical stability of indomethacin arginine CAM (i.e. crystallization of amorphous form) over a broad range of compression pressures for longer duration. Indomethacin showed marked enhancement in dissolution rate as compared to pure crystalline drug but in tablet form it attained low supersaturation than spray

20

dried CAM. However, AUC of dissolution profile of CAM was not affected by formulating CAM into tablet (Lenz et al., 2015). Protection of amorphous form of drug from moisture is a mandatory requirement for stable formulation development. Since, formulation is an important step in drug product development, the other formulation issues like excipient and CAM compatibility, crystallization risk during compression of tablet, influence of external factors such as humidity, temperature and mechanical stress on stability and performance of the CAM must be addressed. Excipients like fumed silica can be incorporated into formulation, which are capable of reducing the moisture uptake by CAM in addition to conferring the required properties for processing and formulating into a desired final dosage form like tablet or capsules. Special focus on packaging system is also needed to circumvent the role of moisture and other stress conditions on stability of the CAM formulation during shelf life. Use of aluminum foil blister or blisters having vacuum or argon atmosphere packaging with moisture absorber or coating of polyvinylidene chloride (PVDC) or polychlorotrifluoroethene (PCTFE) on polyvinyl chloride (PVC) film in blister packaging can increase the efficacy of the packaging for moisture prevention (Pilchik, 2000). Some advanced packaging materials like high barrier thermoformable films, desiccant papers or films, cold formable foils, coupled with color changing cards to indicate moisture levels can assist in maintaining the stability of the CAM formulation during transportation and storage. 3.7 Regulatory approval In the past two decades, few patents of CAM have been granted. This intellectual property protection helps in life cycle management of drug products. These patents satisfy the preliminary criterion for issuing of patents such as novelty (CAM is a new solid form), non obviousness (the

21

physicochemical properties and physical stability are unable to predict) and utility (improvement in physical/ chemical stability, solubility, dissolution and bioavailability, improvement in pharmacological activity and therapeutic benefits via combination of two drugs). Similar to PASD, CAM faces regulatory challenges as it contains amorphous form of drug posing challenge to the manufacturer to maintain and demonstrate stability of amorphous form in order to fulfill quality specifications and for assurance of consistent in vivo response (Rahman et al., 2014). Monitoring and controlling the stability of such amorphous based system is a major regulatory challenge for the final product development. Often the product meets the quality specifications at the time of release but fails in quality control testing such as dissolution, due to aging of product during storage. This type of discrepancy in quality control testing may occur due to presence of 100 % amorphous content during the initial period of testing which may decrease with time due to recrystallization during storage. Presence of numerous PASD based products in the market paves a clear path for commercialization of CAM. Conceptual similarities between CAM and PASD may be useful for applying the same principles for regulatory documentation. Despite the fact that CAM belongs to amorphous based system as that of PASD, more apprehensions has been raised especially to drug-drug CAM, as the combination of two drugs which may or may not have pharmacological relevance creates huge challenge for patient safety. This highlights major regulatory constraint of administering more than one drug in a fixed ratio between the two drugs which need to be addressed. Similarly, in drug-excipient CAM, the coformer selected should also meet the regulatory requirements. These excipients should be of pharmaceutical grade material and must be listed in “Generally Regarded As Safe” (GRAS) category of FDA. Percentage level of excipients that can be used in CAM formulation should also be within the limits specified in FDA-IIG database (FDA- inactive ingredient list). 22

4.

Future perspectives and concluding remarks

Amorphous systems are anticipated to acquire more attention from the pharmaceutical industry in future, because of the growing number of poorly soluble drug candidates. It is expected that the co amorphous approach for stabilization of amorphous drug could hold potential in physical stabilization and improving dissolution of poorly soluble drugs. In last few years, more than 35 research articles and 7 patents were published in this area. This approach is still in infancy and needs detailed research on mechanism of CAM formation, stabilization and its dissolution benefits. Flow chart depicting on proposed scheme to proceed with the development of CAM based products is given in figure 4. Although CAMs are devoid of disadvantages of PASD, complete assurance on stability is not possible as they are amorphous systems which are inherently unstable and have potential to revert back to more stable crystalline form. To date, most of the CAM literature has reported stability studies conducted at 0 % RH condition which might be suitable for lab scale screening and preparation of CAM but are inadequate for commercialization. Accelerated stability study at different temperature and RH is mandatory to achieve the critical quality attributes of final drug product. Current research work on CAM is more focused on preparation and characterization of amorphous system. There is a need of advanced characterization tools to elucidate the formation of CAM and understand the underlying stabilization mechanisms involved, to predict stability of such systems. Similarly, the precipitation behavior of CAM in solution state and recrystallization tendency in solid state needs to be studied. Effect of co-formers on nucleation and crystal growth inhibition needs to be investigated for determining physical stability of CAM as benefits of such supersaturated system can only be achieved if any one of these two steps of crystallization is inhibited by the co-former (Chavan et al., 2016). Further research is required to explore the final 23

dosage form for CAM as amorphous form of drug is susceptible to degradation during manufacturing, processing and storage. Novel preparation methods must be explored at industrial scale as existing techniques fail to convert crystalline drug to a truly amorphous form. Scalable techniques like spray drying and freeze drying can provide potential avenue for development of CAM of drug molecules which are thermally unstable. Potential role of excipients in amorphous stabilization in biological system should be investigated through in vivo studies. Limited availability of drug-drug combinations (pharmacologically relevant) makes it difficult to design a commercially feasible CAM based on fixed dose combination. Identifying molecular descriptors to understand the glass forming ability of drug molecules is also important to develop a stable CAM using appropriate combination of drugs. Alhalaweh et al, developed a computational prediction tool based on two molecular descriptors (the number of hydrogen bond acceptors and Huckel pi atomic charges) which helped in identifying 77 glass forming drugs out of 131 drug molecules. Drug molecules like cimetidine, indapamide, quercetin, and ritonavir are strong glass forming agents and have potential for amorphous stabilization (Alhalaweh et al., 2014). Drug-drug CAM thus provides interesting opportunity for new formulations in combinational therapy that will help in designing synchronized release, even in absence of excipients. Post exploration of carboxylic acids and amino acids as CAM stabilizers, flavonoids would form an ideal platform for exploring possibilities of CAM formation with drugs. Literature reports glass forming ability of few flavonoids like quercetin (Dengale et al., 2015), hespertin, naringenin, fisetin, myricetin, kaempferol etc. They can be explored to investigate CAM formation with drugs and excipients to develop effective combinations. Amicable functionalities via keto and hydroxyl groups available around the flavanol skeleton could render possibilities for 24

intermolecular interactions with drugs containing strong hydrogen bond donors and acceptors. Amino acids have also demonstrated their potential in amorphous stabilization. Among small molecules used for CAM, amino acids are well explored and could be a good starting material for developing CAM. Even though first report on amorphous binary mixture came in 1998, to date only a small fraction of information has been divulged. There are many areas uncharted regarding CAM. To reach the full potential of this approach there is a need to investigate all these unexplored areas.

5. Acknowledgements The authors acknowledge the financial support from the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Govt. of India.

25

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Figure Legends Figure 1: Comparison of co amorphous system with polymeric amorphous solid dispersion Figure 2: Preparation methods for co amorphous system Figure 3: Characterization tools for co amorphous system: DSC- differential scanning calorimetry, DVS- dynamic vapor sorption, IGC-inverted gas chromatography, DES- dielectric spectroscopy, FTIR- Fourier transform infrared spectroscopy, TEM- transmission electron microscopy, AFM- atomic force microscopy, DMA- dynamic mechanical analysis, PXRDpowder X- ray diffractometry, ss-NMR- solid state nuclear magnetic resonance. Figure 4: Flow chart depicting protocol for the preparation of CAM based systems.

30

Figures

Figure 1. Comparison of co amorphous system with polymeric amorphous solid dispersion 31

Figure 2. Preparation methods for co amorphous system

32

Figure 3. Characterization tools for co amorphous system: DSC- differential scanning calorimetry, DVS- dynamic vapor sorption, IGC-inverted gas chromatography, DES- dielectric spectroscopy, FTIR- Fourier transform infrared spectroscopy, TEM- transmission electron microscopy, AFM- atomic force microscopy, DMA- dynamic mechanical analysis, PXRD- powder X- ray diffractometry, ss-NMR- solid state nuclear magnetic resonance.

33

Figure 4. Flow chart depicting protocol for the preparation of co amorphous based systems.

34

Table Legends Table 1: Reported co amorphous systems Table 2: Patents on co amorphous system Tables Table 1 Reported co amorphous systems Sr. CAM Preparation method No. Drug-Drug co amorphous system

Ratio

2

Cimetidine: indomethacin Cimetidine: diflunisal

3

Cimetidine: naproxen

4

Indomethacin: ranitidine Ball milling hydrochloride

1:1

5

Indomethacin: naproxen

1:1

6

Simvastatin: glipizide

1

Solvent evaporation method Solvent evaporation method Ball milling 1:1

Quench cooling

8

Cryo milling and ball 1:1, 1:2 milling Atorvastatin: carvedilol: Solvent evaporation 1:1 glibenclamide method Indomethacin: naproxen Quench cooling 1:1

9

Curcumin: artemisinin

7

Solvent method

evaporation 1:1

Mechanism behind Observation CAM formation

Ref.

Molecular interactions

(Yamamura et al., 2000) (Yamamura et al., 2002) (Alleso et al., 2009)

Improvement in solubility and dissolution of both drugs Molecular interactions Improvement in solubility and dissolution of both drugs Molecular interactions Improvement in stability and intrinsic dissolution rate of both drugs Molecular interactions Amorphization tendency of indomethacin improved when co milled with ranitidine hydrochloride Heterodimer Improvement of stability and formation and dissolution rate of both drugs with molecular interactions synchronized release profile Anti plasticization Improvement in stability of effect of glipizide amorphous simvastatin Molecular interactions Improvement in stability and bioavailability of both drugs Heterodimer Improvement in stability and formation dissolution Molecular Improvement in solubility and interactions, pharmacokinetic profile of curcumin formation of miscible and artemisinin

(Chieng et al., 2009)

(Lobmann 2011)

et

al.,

(Lobmann et al., 2012) (Shayanfar and Jouyban, 2013) (Lobmann et al., 2013b) (Suresh et al., 2014)

35

10

Ritonavir: indomethacin

Solvent method Solvent method

evaporation 2:1

11

Ritonavir: quercetin

12

Ezetimibe: indapamide

13

1:1

14

Nateglinide: metformin Ball milling hydrochloride Talinolol: naringin Quench cooling

15

Glipizide: atorvastatin

Cryo milling

1:1

16

Naproxen–indomethacin

Spray drying

-

evaporation 1:2

Quench cooling

Omeprazole-amoxicillin Co-grinding trihydrate Tranilast and Quench cooling 18 Diphenhydramine Hydrochloride Indomethacin: Quench cooling, 19 cimetidine and co precipitation and naproxen: cimetidine ball milling Drug-Excipients co amorphous system 17

Saccharine Repaglinide: saccharine 20

Solvent method

10:1

1:1, 2:1

3:7, 1:1, 7:3 1:1

1:1

evaporation 1:1

system Anti plasticization effect Glass forming ability of quercetin

Improvement in dissolution rate of (Dengale et al., ritonavir 2014) Improvement in saturation solubility (Dengale et al., 2015) of ritonavir

Glass forming ability Improvement in stability of of indapamide ezetimibe at low levels (8.8 wt %) of indapamide. Proton exchange Improvement in solubility and dissolution of nateglinide. Molecular Improvement in solubility and interactions, bioavailability of talinolol. formation of miscible system Dissolution enhancement and improved physical stability. Molecular interactions Formation of drug–drug heterodimers in the co amorphous phase due to simultaneous recrystallization of both the drugs from the spray dried CAM. Molecular interactions Improvement in solubility

(Knapik et al., 2015)

(Wairkar and Gaud, 2015) (Teja et al., 2015)

(Renuka et al., 2015) (Beyer et al., 2016)

(Russo et al., 2016)

Molecular interactions Improvement in physical stability up (Ueda et al., 2016a) and reduced molecular to 30 days. mobility Molecular relaxation Structural relaxation is found to be (Lim et al., 2016) dependent on CAM preparation method

Molecular interactions

Improvement in solubility and (Gao et al., 2013) dissolution. Saccharine prevents aggregation of repaglinide during the dissolution. 36

Lurasidone Solvent evaporation hydrochloride: method saccharine Amino acids Carbamazepine: Ball milling 22 tryptophan and indomethacin: phenyl alanine and arginine Naproxen: proline 23 21

1:1

Molecular interactions

1:1, 1:1:1

Molecular interaction Improvement in dissolution and (Lobmann and elevated Tg stability. 2013a)

1:1

Molecular interactions

24

Glibenclamide: serine, simvastatin: lysine

Cryo milling

1:1

25

Indomethacin: arginine Spray drying tablet preparation

1:1

26

Indomethacin: Ball milling tryptophan and furosemide: tryptophan Valsartan with L- Vibrational histidine, L-arginine, milling and L-lysine

1:1

27

ball 1:1, 1:1:1

28

Simvastatin: lysine (5 % Spray Drying Sodium Lauryl Sulfate (SLS))

1:1

29

Indomethacin: Ball milling tryptophan, arginine and furosemide: tryptophan, arginine

Varying molar ratio

Improvement in dissolution and stability

solubility, (Qian et al., 2015)

et

al.,

Improved stability of naproxen by (Jensen et al., 2014) proline Amino acids might Improved stability and dissolution of (Laitinen et al., interfere drug-drug both drugs in CAM prepared with 2014a) interactions and delay receptor amino acids the crystallization Enhanced stability of spray dried (Lenz et al., 2015) CAM during tableting with immediate release of indomethacin by erosion from tablet. Molecular interactions Improvement in solubility and (Jensen et al., 2015) dissolution of both drugs. Molecular interactions between carboxylic acid group of valsartan and the amino groups of amino acids Formation of weak molecular interactions between simvastatin and lysine was disrupted by SLS Molecular interactions

Improvement in physical and (Huang et al., 2016) chemical stability of amorphous valsartan with enhanced dissolution rate Improvement in amorphous (Craye et al., 2015) stabilization of simvastatin: lysine CAM in presence of SLS.

Tg of CAM with varied molar ratio (Jensen et al., 2016b) helped in predicting the Tg of a single amorphous compound which was difficult to determine experimentally. 37

30

Indomethacin: arginine

Nicotinamide Atorvastatin 31 nicotinamide

calcium: Solvent method

Carboxylic acids Indomethacin: citric acid 32

33 34 35

36

Spray drying

1:1

evaporation 1:1

Melt quenching

-

Strong intermolecular 200 fold enhancements in IDR of interactions leading to indomethacin salt formation Molecular interactions

Improvement in solubility, intrinsic (Shayanfar dissolution rate, and plasma 2013) concentration of atorvastatin.

et

Molecular interactions

Citric acid and indomethacin miscible up to 0.25 weight fraction of citric acid Improvement in stability Improvement in solubility and dissolution of clozapine. Improvement in dissolution rate of β-azelnidipine

Zografi,

Paracetamol: citric acid Clozapine: carboxylic acid β-azelnidipine and maleic acid

1:1 Solvent evaporation 1:1.5 method Neat powder 1:1, 1:2 grinding and solventassisted grinding Sulfathiazole: L-tartaric/ Co milling 1:1 citric acids

37

Acyclovir: citric acid

38

Sulfamerazine: deoxycholic acid/ citric acid/ sodium taurocholate

Solvent evaporation method Oscillatory ball mill -

(Jensen et al., 2016a)

-

(Lu and 1998)

al.,

(Hoppu et al., 2007) (Ali et al., 2015) (Han et al., 2016)

CAM of sulfathiazole with tartaric (Hu et al., 2014) and citric acid was stable up to 28 days at 10 % RH Improvement in stability and in vitro (Masuda et al., 2012) skin permeation flux Significant enhancement in (Gniado et al., 2016) dissolution rate with sulfamerazine and sodium taurocholate CAM.

38

Table 2 Patents on co amorphous system Patent no. CN103360357A

Composition Simvastatin-gliclazide

Ratio 2:1

CN103497178A CN104693181A

Irbesartan-repaglinide Azelnidipine - maleic acid

1:1 1:1,1:2

CN103467363A CN104415042A

Carvedilol-saccharine 1:1 Pioglitazone hydrochloride- 1:1 glimepiride Baicalein-caffeine 1:1

CN103923049A

Observation Solid state characterization tool indicated formation of stable CAM of simvastatin and gliclazide Improvement in solubility of both drugs Drug was present in amorphous form when combined with maleic acid in different proportions. Improvement in solubility of carvedilol in water and in different pH Strong intermolecular interaction led to formation of stable CAM Improvement in dissolution of baicalein

39