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Pastillation: A novel technology for development of oral lipid based multiparticulate controlled release formulation
Powder Technology 209 (2011) 65–72
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Powder Technology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c
Pastillation: A novel technology for development of oral lipid based multiparticulate controlled release formulation Dali Shukla, Subhashis Chakraborty, Sanjay Singh, Brahmeshwar Mishra ⁎ Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi 221005, India
a r t i c l e
i n f o
Article history: Received 8 May 2010 Received in revised form 28 January 2011 Accepted 11 February 2011 Available online 18 February 2011 Keywords: Pastillation Pastilles Doxofylline Controlled release Lipid Stearic acid
a b s t r a c t A novel technique, ‘Pastillation’ to fabricate lipid based oral multiparticulate controlled release dosage forms for first time in pharmaceutical field is reported. An in-house laboratory scale device was designed to generate pastilles of doxofylline loaded stearic acid. Pastilles formed were characterized for drug content uniformity, drug release profile, morphology and contact-angle. The optimized conditions for pastillation were 1.00 cm dropping height, 20 G needle orifice and 4 °C plate temperature which produced good pastilles of uniform size (2.5– 3.0 mm) with contact angle above 90°. This multiparticulate system has very good flow property and is very uniform in size, weight and drug content and is able to sustain the drug release for a period of 24 h. This is a very simple method for producing lipid-based multi-particulate system as compared to other available techniques (melt-extrusion and freeze-pelletization) which can further be filled in capsules/sachets. The biggest advantage of this technology is that the large-scale equipment for pastillation is well-established in chemical industries. Therefore, use of this unique dosage form may open new avenue in the field of drug delivery which may even be an alternative for line extension or preparing patent non-infringing products of existing formulations. © 2011 Elsevier B.V. All rights reserved.
1. Introduction For chronic treatment, the oral controlled release drug delivery systems represent the most popular form of dosage forms. Such systems release the drug at constant rate and offer many advantages, such as nearly constant drug level at the site of action, minimum peakvalley fluctuations, reduction in dose of drug, reduced dosage frequency, avoidance of side effects, and improved patient compliance [1,2]. These formulations show a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time (sustained release), thereby ensuring sustained therapeutic action [3]. A controlled release multiparticulate system consists of multiple mini drug depots wherein the drug is either dispersed in a matrix or encapsulated in a reservoir. They are diverse in size which may vary from nano to milli scale. They are generally termed as nanoparticles, microparticles, microcapsules, pellets, minitablets and granules, which can be administered in a single dose by compressing into a dispersible tablet or filling into capsule or a sachet, in case of high dose. They can be manufactured by the agglomeration of fine powders or granules of the drug substance and excipients using appropriate processing technology and equipment. The current pharmaceutical technology has already realized the tremendous potential of controlled release multiparticulate system in ⁎ Corresponding author. Tel.: + 91 5426702748; fax: + 91 542 2368428. E-mail addresses: [email protected] (D. Shukla), [email protected] (B. Mishra). 0032-5910/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2011.02.006
terms of its flexibility in product development and therapeutic benefits to the patients in comparison to the conventional single unit dosage form. The release of drug from any modified release dosage form, of multiple strengths, changes as a function of its surface area. In case of matrix tablets of different dosage strengths, if the same blend is compressed at different weights, the change in surface area (due to change in tablet dimension) is not usually proportional to its dosage strength which results in altered drug release profile. While in case of multiparticulate system, microparticles can be divided as per the desired dosage strengths without any effect on the dimension of the individual particles. Therefore, the overall surface area of a dosage form changes proportionately with the dosage strength which does not significantly alter the drug release profile. This eases the process of scale up and scale down and reduces the extra time and cost incurred in carrying out bioequivalence studies for all other strengths. Moreover, they can also be used for delivery of incompatible drugs together or to administer drugs at different release rates in the gastrointestinal tract. When administered orally, they generally disperse uniformly in the gastrointestinal tract, maximize absorption, minimize localized side effect and reduce intra and inter subject variability [4]. Multiple unit system can also offer added advantages of prolonged gastrointestinalresistance and shorter absorption lag-time [5]. 2. Theory The present research work involves the use of wax/lipid as a major excipient in the product development. Several techniques are available in literature for the processing of waxy/lipid excipients,
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viz., melt granulation [6], melt extrusion [7], pastillation [8], melt dispersion [9], and melt solidification [10] for multi-particulate product development. Except pastillation, all other techniques have been explored for their potentials in drug delivery. Pastillation is a widely used technique in chemical, petrochemical and agrochemical industries for the solidification of dusty hazardous powders of chemicals into pastilles (hemispherical solidified units of uniform size) which eases their handling. In this process, the drops of chemical substances in molten state are deposited on a cooled stainless steel surface for rapid solidification to generate pastilles of uniform dimensions. Depending on the size of the drops and the physical properties of the melt, the drops flatten to a certain extent. The solidified droplet, therefore, has the typical pastille-like shape. The production process can easily be carried out at large scale with the help of specially designed equipments called ‘Rotoformer’ [11]. Therefore, the objective of the present work was to explore the pastillation technology for the development of immediate and controlled release multiparticulate drug delivery system. Briefly, the operating parameters for the fabrication of pastilles were optimized and then the effect of the excipients on the in vitro drug release from the dosage form was studied along with their morphological and solid state characterization. Doxofylline [12], an anti-asthmatic drug used for treatment of asthma and chronic obstructive pulmonary disorder has been used for the present study. 3. Materials and methods 3.1. Materials Doxofylline was a kind gift from Euro Drugs, Hyderabad, India. Polyethylene glycol (PEG) 400, PEG 4000 and PEG 6000 were procured from Ranbaxy Laboratories Ltd. (India). Stearic acid, colloidal silicone dioxide (Aerosil 200) and benefat were generous gifts from Witco Chemicals (Newark, NJ), Degussa (Germany) and Danisco (Denmark), respectively. All other ingredients were of analytical grade and were used as received. 3.2. Methods 3.2.1. Fabrication technology A laboratory scale device was designed in-house for producing pastilles as shown in Fig. 1 [13]. The device consisted of a glass syringe with stainless steel plunger, hypodermic needles (metallic), a metallic plate, heating coil and a 1.5 A transformer. The heating coil was wrapped on the external surface of an open ended ceramic tube and coated with a thick layer of ceramic clay for insulation. The coil was then connected with the transformer before being connected to electricity. The syringe with hypodermic needle attached was inserted into the ceramic tube. This assembly was arranged over the metallic plate with the help of a burette holder. The metallic plate was cooled with the help of ice cubes in the ice tray placed below it. The drug and other required excipients were added to the lipid/PEG melt under heating condition (140–150 °C) and were manually stirred till a clear miscible mixture was produced, which ensures homogenous distribution of drug in the matrix. The mixture was then poured into the preheated syringe and was allowed to fall drop-wise (with pressure regulation managed manually with plunger of the syringe) on to the cold plate to generate pastilles (Fig. 1 insets). After solidification, the pastilles were scrapped with the help of a sharp metallic scrapper. They were then manually filled into size ‘0’ capsules. The operating parameters for the fabrication of the pastilles were optimized using 23 factorial design. Three operating variables are needle (orifice) size (X1), dropping height (distance between the needle tip and plate surface) (X2) and temperature difference between the plate and melt (as the temperature of melt was kept constant, only temperature of plate was studied as third variable) (X3)
Fig. 1. In-house laboratory design of pastillation device [13].
each at two levels were studied on placebo batches prepared with stearic acid (Table 1). The effect of these factors was studied on the contact angle (Y1) of the pastilles as the response variable which was evaluated using MINITAB software. Table 2 shows the operating and the response variables. The optimized operating parameters obtained from the above experiments were then employed for the further preparation of batches on the basis of their flow property as presented in Table 3. 3.2.2. Contact angle measurement Contact angle of the solidified hemispherical drops i.e. pastilles was measured against solid stainless steel plate by photographic method [14]. The photographs of the pastilles were taken from the horizontal side at their contact with the plate and the snaps were then proportionally magnified and processed using Adobe Photoshop® software. The angle of contact was determined manually and confirmed mathematically using the following equation: −1
θ = 2tan
2h = d
Where h is the height of the drop from the plate and d is the diameter of the drop. Both of these dimensions can be measured from the photograph for calculating the contact angle. 3.2.3. Analytical method The standard curves of doxofylline were prepared in water, 0.1 N HCl (pH 1.2) and phosphate buffer solutions (pH 6.8) in the concentration range of 5–35 μg/ml. The solutions were analyzed by UV–VIS spectrophotometry (Hitachi U-1800). A UV visible spectrum of doxofylline showed a characteristic peak at 273 nm in all the solutions. The standard curve was plotted as drug concentration (μg/ ml) vs. absorbance plot. Curve fitting was done by linear regression analysis using Microsoft Excel program (Version 2007). Table 1 Factorial design parameters and experimental conditions. Sl No.
Factors
Low (−)
High (+)
1. 2. 3.
Needle dimensions (X1) Dropping height (X2) Temperature of plate (X3)
16 G 1 cm 4 °C
20 G 3 cm 25 °C
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4.2. Effect of operating variables on contact angle
Table 2 Formulation of the pastilles utilizing 23 factorial design. Sl. no.
Batches
X1
X2
X3
Avg. Contact angle (Y1)
1. 2. 3. 4. 5. 6. 7. 8.
A1 A2 A3 A4 A5 A6 A7 A8
16 G 16 G 16 G 16 G 20 G 20 G 20 G 20 G
1 cm 1 cm 3 cm 3 cm 1 cm 1 cm 3 cm 3 cm
4 °C 25 °C 4 °C 25 °C 4 °C 25 °C 4 °C 25 °C
121° 110° 100° 80° 120° 115° 95° 85°
3.2.3.1. Drug content uniformity. For drug content uniformity, pastilles equivalent to 10 mg of doxofylline were transferred individually into a 10 dry 25 ml volumetric flasks. 20 ml of distilled water at 75 °C was added and was sonicated in an ultrasonic water bath for 10 min while swirling occasionally. Then it was allowed to cool to room temperature. Volume was made up to the mark with distilled water. Ten milliliters of the above solution was filtered through 0.45 μm nylon filter, diluted appropriately with distilled water and was analyzed spectrophotometrically at 273 nm. Blank solution was prepared by similar treatment of placebo batches as described above in order to avoid interference due to the presence of excipients. 3.2.3.2. Drug release study. Drug release studies were carried out on six units using USP Dissolution Apparatus II (Erweka DT-6) using 500 ml of 0.1 N HCl as dissolution medium at 50 rpm and 37 ± 0.5 °C for 2 h followed by pH 6.8 phosphate buffer for next 22 h. Five milliliters of aliquots were withdrawn at predetermined intervals with replacement. The samples were filtered using 0.45 μm nylon filter and finally analyzed by UV spectrophotometer at 273 nm. 3.2.4. Scanning Electron Microscopy The morphological structure of the prepared pastilles was observed using scanning electron microscope (FEI Quantum 200E Instrument). 3.2.5. Stability study Pastilles of B-10 batch were packed in 30 ml HDPE bottles, sealed and kept at 40 °C maintained at 75% relative humidity in stability chamber (Narang Scientific Works Pvt. Ltd., New Delhi, India) for a period of 3 months as per ICH guidelines. Samples withdrawn at 1, 2 and 3 months were analyzed for drug content and drug release test. 4. Results and discussion
Contact angle of the pastilles is a measure to evaluate the spreading of a drop of melt on the plate surface before it gets solidified. The effect of various operating variables like needle size, height of needle from plate and temperature of plate on the contact angle was studied using 23 factorial design and the results are tabulated in Table 2. The primary study to optimize the operating variables was carried out using stearic acid alone (without drug). The optimized parameters were then employed for fabrication of further batches. 4.2.1. Needle size From the contour plots of contact angle vs. needle size and height of plate (Fig. 2), it was observed that at a constant plate temperature of 4 °C and variable height of plate, the contact angle of pastilles does not vary with the change in needle size. Similarly, in contour plot of contact angle vs. needle size and temperature of plate (Fig. 3), at constant height difference of 1 cm and at low temperature of plate, the contact angle is high at 16 G needle size. This effect of needle size subsides when the plate temperature is reduced gradually. Thus, it is clearly evident that needle size does not affect the contact angle remarkably and therefore, the shape of formed pastilles remains unaffected. However, the size of the pastilles increases from 2.0 ± 0.1 mm to 4.3 ± 0.2 mm with increase in the needle orifice diameter (size) from 20 G to 16 G. Further reduction in needle size beyond above range would result in difficulty in passage of melt from the needle and increase from this range can form pastilles with bigger size which cannot be filled in capsule. 4.2.2. Dropping height Effect of dropping height i.e. height difference of needle from the plate on contact angle of pastilles was also studied and was found to have an inverse relation with the contact angle as with increase in the dropping height, there was a significant decrease in the contact angle with constant plate temperature (4 °C) and needle size (Fig. 2). Similar observation was made in contour plots of contact angle vs. temperature of plate and height of needle (Fig. 4). With decrease in dropping height, the impact or force with which the drop strikes the cold surface reduces. This reduces the extent of spreading of the drop which immediately solidifies by transfer of its heat to the cold plate. The contour plots (Fig. 2 and 4) suggest that irrespective of the needle size and temperature of the plate, dropping height of ≤1.5 cm would be ideal for fabrication of pastilles with higher contact angles. Further decrease or increase in dropping height may not be possible.
4.1. Selection of excipients The excipients were selected based on the type of dosage form to be developed. For immediate release formulations, PEG was selected as the matrix former due to its water soluble nature. For controlled release formulations, stearic acid, a solid lipid (melting point ~70 °C) was selected as the matrix base due to its hydrophobic nature. PEG and benefat, a liquid lipid (at body temperature), have been used as poreformer and drug release rate modifier for the controlled release batches. Colloidal silicon dioxide was employed in some batches to improve the viscosity of the melt. Table 3 Flow property of pastilles based on their contact angle. Flow property
Contact Angle
Poor Fair Good
60–85° 85–105° 105–125°
Fig. 2. Contour plot to elaborate effect of needle size and height of needle from plate on contact angle of pastilles.
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uniformly distributed in the matrix. In addition, it also indicates that the drug does not undergo any possible degradation due to its exposure to high temperature during fabrication and is, therefore, thermostable. 4.4. Drug release study The solubility studies for the drug carried out in our laboratory indicated the maintenance of sink condition of the drug in the selected dissolution medium. Two different types of matrix forming agents (PEG and stearic acid) were used in the preparation of the pastilles. PEG based pastilles (B-1) showed immediate drug release within 45 min (Fig. 6) due to its highly hydrophilic property.
Fig. 3. Contour plot to elaborate effect of needle size and temperature of plate on contact angle of pastilles.
4.2.3. Temperature of plate At low plate temperature, sudden cooling of the drop takes place that hinders its spreading on the plate and the pastille is formed instantaneously with high contact angle. At higher plate temperature, the drop takes time to cool and solidify that provides sufficient time to drop before its spreading is stopped by solidification. Therefore, the contour plots of contact angle vs. temperature of plate and needle size and contact angle vs. temperature of plate and height of needle (Figs. 3 and 4) suggests that irrespective of the height difference and needle size, maintenance of low plate temperature (4 °C) is essential for generating pastilles of high contact angle. Further reduction in temperature can enhance contact angle by minimizing the spreading time. However, further increase in the rate of solidification may result in porous pastilles due to sudden cooling. Moreover, provision to reduce and maintain the plate temperature below 4 °C would require elaborate and sophisticated instrumentation which would add high cost to the production technology. Therefore, further change in optimized temperature may not be possible. The photographs taken during the study indicated that any contact angle greater than 90° demonstrates sufficient spherical nature of the pastilles than those with lower angles. The higher contact angle is desirable as it represents the pastilles with hemispherical shape which imparts good flow ability during large scale handling. The above observations are summarized in Table 3. Based on the above observations and the results of the contour plots, 1 cm height difference of needle from the plate and 4 °C temperature of plate were found to be the optimum parameters to generate pastilles of good contact angle. Reduced height difference results in lower impact with which the drop strikes the plate and low plate temperature will reduce the spreading time. High spreading time will give non spherical particle and will result in short contact angle followed by decrease in spherical nature of pastilles. Both these parameter assist in increasing the contact angle and hence increase the spherical nature of pastilles. 20 G needle size was selected as it produced pastilles of smaller dimension which could easily be filled into size ‘0’ capsules. Immediate release pastilles (B-1) using PEG in place of stearic acid were also prepared using the above optimized parameters and their contact angles were measured. The pastilles were very thin with large diameter and poor contact angles (b80 °C). This is due to relatively low viscosity and high spreadability of the PEG melt. Therefore, its viscosity was enhanced by addition of colloidal silicon dioxide which helped to improve its contact angle to 95°. The contact angles of pastilles of B-1 and B-10 (controlled release pastilles of stearic acid) are shown in Fig. 5.
4.4.1. Effect of release medium composition on drug release An interesting observation was made when the drug release study of the stearic acid pastilles (Batch B-2) was being carried out in pH 6.8 phosphate buffer (USP) after 2 hrs of study in 0.1 N HCl. The drug was completely released within 8 hrs (Fig. 6) and during release study the pastilles acquired a swollen disc shape which was very soft and creamy and could be easily deformed. There was a significant difference in the shape and size of pastilles before and after drug release study (Fig. 7A). The pastilles during drug release study in pH 6.8 phosphate buffer (USP) are shown in Fig. 7B. However, no change in shape, size and strength of pastilles was observed after dissolution in 0.1 N HCl. Based on the above observation, an incompatibility of the lipid with the buffer components was suspected. Therefore, the composition of 6.8 pH phosphate buffer was changed with mixed sodium buffer i.e. Na2HPO4 and NaH2PO4 which drastically changed the drug release pattern as shown in Fig. 6. The drug release was retarded to 24 h and the issues related to swelling and softening of the pastilles were also eliminated (Fig. 7C). Finally the incompatibility presumed was confirmed which may be related to the incompatibility of stearic acid with metal hydroxides [15], to form water soluble sodium salt of stearic acid. Hence, the dissolution of further batches was carried out in mixed sodium pH 6.8 buffer. The drug release from B-2 with only stearic acid in the matrix was very slow with only 24% of release in 24 h (Fig. 6). This is due to the highly hydrophobic lipid matrix and the absence of an additional pore former which together prevent the access of the aqueous medium into the inner layers. The amount of drug that was released may be the surface adsorbed drug along with the drug embedded within the matrix, which the medium could solubilize due to the pore forming ability of the water soluble drug. Here the drug release is controlled by diffusion and dissolution of the drug in the water filled pores of the matrix. In order to improve the drug release, two approaches were
4.3. Drug content uniformity The drug content values of batches B-1 and B-10 are presented in Table 4. The drug content uniformity values show that the drug is
Fig. 4. Contour plot to elaborate effect of temperature of plate and height of needle from plate on contact angle of pastilles.
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Fig. 5. Contact angle of pastilles measured by photographic method.
released in two hours after which controlled release with more than 90% drug release in 24 hrs was achieved only in case of B-4. However, the rapid drug release in the initial stage was required to be controlled which is due to faster solubilization of drug and PEG present at the surface. The remaining drug release from the pastilles is solely dependent on the mechanism of diffusion.
applied. PEG, a water soluble agent was incorporated in the lipid matrix to act as a pore former. In the second approach, benefat, a low melting lipid (liquid at body temperature) was included which could reduce the crystalline integrity of the lipid matrix and also gradually create crevices by separating from the solid matrix after melting at body temperature.
4.4.3. Effect of drug load The drug release rate increased with increase in the drug load as shown in Fig. 8. As lipid/drug ratio reduces, amount of lipid available to control the release of drug decreases, resulting in faster drug release from the matrix.
4.4.2. Effect of presence and type of poreformer Three grades of PEG (PEG 4000, PEG 6000 and PEG 400) were used as poreformer (B-3, B-4 and B-5) and their drug release profiles are presented in Fig. 6. Addition of PEGs as a poreformer was found to increase the drug release rate. As the matrix is exposed to the aqueous medium, PEG and the drug on the surface starts to dissolve which provides space for the aqueous medium to gain access to the lower lying layers. This continuous process generates pores with increasing network within the matrix. The release rate was fastest with PEG 6000 than PEG 4000 and slowest with PEG 400. This pattern of release rate may be attributed to their physical state, molecular weight and hydrophilicity. As the molecular weight of PEG increases, their melting point increases. PEG 400 being liquid in nature forms channels faster than other two PEGs which are solid at 37 °C and therefore, takes time to solubilize. However, in the liquid state, size of the pores formed is relatively smaller during solidification of the melt. PEG 400 being in the liquid state is homogenously distributed throughout the matrix. In case of solid PEGs, they form bigger pores due to their significantly higher molecular weight. This is exemplified by the faster drug release rate of batch B-4 than batch B-3 as molecular weight of PEG 6000 is higher than PEG 4000 which results in comparatively bigger channels. Overall, about ≤ 30% of drug was
4.4.4. Type of lipid combination Benefat is a mixture of triacylglycerols containing short chain (acetic, propionic, and/or butyric acids) and long chain (stearic acid, canola and soybean oil) fatty acids with stearic acid as the predominant long chain fatty acid (58 to 67 g per 100 g triacylglycerol) [16]. It is semi-solid at room temperature and melts to a clear liquid at body temperature. The drug release profiles of batches with benefat (Batches B-8, B-9 and B-10) are shown in Fig. 9. In batch B-8, the release profile was almost similar to that of batch B-3 with a slight reduction in initial release, as expected due to the hydrophobic nature of benefat. At the same time, a reduction in the pastille strength was observed due to the presence of excess amount of liquid lipid which interfered with their crystalline integrity. The batches failed to withstand the agitation and therefore, could not maintain their integrity in the medium during the dissolution study. Pastilles with reduced amount of benefat (Batch B-9) or without
Table 4 Formulation composition of the prepared batches using pastillation technique. Composition
DOX Stearic acid Benefat PEG 4000 PEG 6000 PEG 400 Colloidal slilcon dioxide Drug content Uniformity(%)
mg/batch B-1
B-2
B-3
500
500 2000 – – – –
500 2000 – 300 – –
2000
75 100.56 ± 0.93
B-4 500 2000 – – 300 –
B-5
B-6
B-7
B-8
B-9
B-10
500 2000 – – – 300
300 2000 – 300 – –
400 2000 – 300 – –
500 1700 300 – – –
500 1700 150 – – –
500 1700 75 – – – 98.89 ± 1.23
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Fig. 8. Drug release profiles showing effect of drug load on drug release of pastilles. Fig. 6. Drug release profiles showing effect of pore former on drug release behavior of pastilles.
benefat (Batch B-1) were found to have sufficient strength to withstand the agitation of the drug release condition. The initial drug release rate was controlled with a linear profile (R2 = 0.985) achieved in case of batch B-10.
faster solidification rate and higher viscosity of the melt. The drop with high viscosity does not get time to spread too much due to faster solidification and low spreadability. The magnified view of B10 (Fig. 10D) showed presence of pores on the upper surface probably formed because of the high rate of solidification which prevents the proper spreading of the melt. 4.6. Stability study
4.5. Scanning electron microscopy The photomicrograph of pastille of B-1 showed a very smooth and uniform texture with a round structure (Fig. 10A). Another picture at higher magnification (Fig. 10B) revealed its highly crystalline and porous matrix. The high porosity and high solubility of PEG in water are the major reasons for fast drug release from the PEG based matrix. On the other hand, pastille of B-10 also has round structure (Fig. 10C), but is smaller in size than B-1 pastille due to its
On comparing the stability data of the stored samples with that of the initial samples, it was observed that neither the physical appearance nor the drug release profiles of the stored samples were influenced by the storage condition (Fig. 11). No change in drug content of the formulation was found (1 M-98.66%, 2 M-97.12%, 3 M96.46%). This indicates that the lipid excipient of the formulation is physically stable and capable of withstanding the environmental fluctuations.
Fig. 7. Incompatibility of drug carrier with composition of dissolution medium (A) pastilles before and after dissolution in pH 6.8 phosphate buffer (USP), (B) pastilles during drug release study in pH 6.8 phosphate buffer (USP), (C) pastilles during drug release study in pH 6.8 mixed sodium phosphate buffer.
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Fig. 9. Drug release profiles showing effect of lipid composition and type of pH 6.8 phosphate buffer media on drug release behavior of pastilles.
5. Limitations of the technology This technology is particularly applicable to carriers of low melting points which melt and are capable of re-solidification at room tem-
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Fig. 11. Comparison of drug release profiles of initial and stability samples of final batch.
perature i.e. lipids, waxes and macrogols. In addition, as the fabrication process involves the use of temperature for melting the excipients, the drug being incorporated should not be degraded during processing, i.e. it must be thermostable in the processing temperature range.
Fig. 10. Morphological study of pastilles by Scanning Electron Microscopy (A) Batch B1 (B) Batch B1 at higher magnification (C) Batch B10 (D) Batch B10 at higher magnification.
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6. Conclusion Pastillation technology was successfully used to fabricate the controlled release pastilles of uniform size and with 24 h drug release controlling ability using lipids as a carrier and release rate modifier. This technology is very simple for producing lipid-based multiparticulate system, as compared to the other available techniques (melt-extrusion and freeze-pelletization), which can further be filled into capsules/sachets as the final dosage form. 7. Future perspective The present study involves the development of a new dosage form of lipid based multiparticulate system for controlled drug delivery by oral route using pastillation. A major advantage with this formulation is that it can be easily scaled-up with the existing pastillation equipment that is well established in the chemical industry. Therefore, this dosage form with a unique dimension may open a new avenue in the field of drug delivery which may even be an option for line extension or preparing patent non-infringing formulations of existing drug products. Use of lipids as the major excipient would also be helpful in reducing the dosage of the drug, especially poorly water soluble drugs [17]. Furthermore, the immediate release pastilles prepared in the present study, if amalgamated with appropriate taste and color, would add as a new item in the product basket of dosage forms for oral delivery. Acknowledgment The first author gratefully acknowledges the financial assistance provided by Indian Council of Medical Research, New Delhi, India, in the form of Senior Research Fellowship to support this research work. References [1] A.R. Gennaro (Ed.), Remington: The Science and Practice of Pharmacy, 20th ed, Lippincott, Williams & Wilkins, USA, 2000. [2] T. Bussemer, I. Otto, R. Bodmeier, Pulsatile drug delivery systems, Crit. Rev. Ther. Drug Carrier Syst. 18 (2001) 433–458. [3] N.G. Das, S.K. Das, Controlled release of oral dosage forms, Formulation, Fill and Finish, 2003, pp. 10–16www.pharmtech.com. [4] H. Bechgaard, G.H. Nielsen, Controlled-release multiple-units and single-unit doses — a literature review, Drug Dev. Ind. Pharm. 4 (1978) 53–67. [5] Y. Ito, H. Arai, K. Uchino, K. Iwasaki, N. Shibata, K. Takada, Effect of adsorbents on the absorption of lansoprazole with surfactant, Int. J. Pharm. 289 (2005) 69–77. [6] T. Schaefer, P. Holm, H.G. Kristensen, Melt granulation in a laboratory scale high shear mixer, Drug Dev. Ind. Pharm. 16 (1990) 1249–1277. [7] J.L. White, W. Szdlowski, K. Min, M.H. Kim, Twin screw extruders: development of technology analysis of flow, Adv. Polym. Technol. 7 (1987) 295–332. [8] J.W. Kim, J. Ulrich, Prediction of degree of deformation and crystallization time of molten droplets in pastillation process, Int. J. Pharm. 257 (2003) 205–215. [9] C.M. Adeyeye, J.C. Price, Development and evaluation of sustained release ibuprofen-wax microspheres. I. Effect of formulation variables on physical characteristics, Pharm. Res. 8 (1991) 1377–1383. [10] A.R. Paradkar, M. Maheshwari, A.R. Ketkar, B. Chauhan, Preparation and evaluation of ibuprofen beads by melt solidification technique, Int. J. Pharm. 255 (2003) 33–42. [11] http://www.processsystems.sandvik.com/. [12] S. Chakraborty, D. Shukla, B. Mishra, S. Singh, Lipid — an emerging platform for oral delivery of drugs with poor bioavailability, Eur. J. Pharm. Biopharm. 73 (2009) 1–15. [13] D. Shukla, S. Chakraborty, S. Singh, B. Mishra, Lipid based oral multiparticulate formulations — advantages, technological advances and industrial applications, Expert Opin. Drug Deliv. 8 (2011) 207–224.
[14] W. Gutowski, Thermodynamics of adhesion, in: Lieng-Huang Lee (Ed.), Fundamentals of adhesion, Plenum Publishing Corporation, New York, 1991, pp. 87–136. [15] R. Mahalingam, X. Li, B.R. Jasti, Semisolid dosages: ointments, creams and gels, in: S.C. Gad (Ed.), Pharmaceutical Manufacturing Handbook: Production and Processes, John Wiley and Sons, Inc, New Jersey, 2008, pp. 267–312. [16] M.T. Tarrago-Trani, K.M. Phillips, L.E. Lemar, J.M. Holden, New and existing oils and fats used in products with reduced trans-fatty acid content, J. Am. Diet. Assoc. 106 (2006) 867–880. [17] D. Shukla, S. Chakraborty, S. Singh, B. Mishra, Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease, Expert Opin. Pharmacother. 10 (2009) 2343–2356.
Dali Shukla is a Senior Research Fellow in Banaras Hindu University. She has an experience in formulation research development for 3 years in Lupin Research Park and Sandoz Pvt. Ltd, India. She has expertise in technology transfer of several immediate release products and is well versed in granulation, compression, coating and capsule filling. Her current area of research is lipid based oral multiparticulate formulations. She has 15 publications and has presented/co-authored 9 research works in national/ international journals/conferences. She has been awarded International Travel Fellowship of DBT, New Delhi and CCSTDS, Chennai, for presenting her research work in the Australasian Pharmaceutical Science Association conference, Australia in 2009. She is recipient of the prestigious AU-CBT Excellence Award of Biotech Research Society, India.
Subhashis Chakraborty, a Senior Research Fellow, Banaras Hindu University has an industrial research experience in formulation development for 3 years in Lupin Research Park, and Sandoz Pvt. Ltd. He has expertise in granulation, tablet compression, coating, fluidized bed pelletization and extrusion–spheronization. His current area of research is lipid based oral nanoparticulate formulations. He has 15 publications in international journals and has reviewed for many journals. He has presented/co-authored 11 research works in national/international conferences. He has been awarded International Travel Fellowship of DST, New Delhi, for presenting his research work in Australasian Pharmaceutical Science Association Conference, Australia in 2009.
Sanjay Singh has a research career span of nearly 20 years in the development of novel drug delivery systems for improved therapeutic performance and patient compliance. He has authored/co-authored 65 research/review articles in national/international journals, presented 44 papers in conferences and published one chapter in a book. He is a reviewer of many national/international journals. His current research interest involves the development and pharmacological evaluation of nanomedicines. He has projects of approximately worth Rs. 70 lacs. He is also a reviewer of various national and international journals and research projects. He has supervised 2 PhD and 19 M. Pharm. students till date.
B. Mishra has major scientific contributions in areas the of drug delivery, bioavailability enhancement, pharmacokinetic and pharmacological evaluation. He has developed stomach targeted floating formulations of clarithromycin and amoxicillin for treatment of Helicobacter pylori induced diseases and various other drug delivery systems for effective and safe management of pain, inflammation, diabetes and amoebic colitis. His current area of interest is development of multiparticulate formulations for controlled and targeted delivery. He has supervised 7 students for Ph.D. and 33 students for M. Pharm., published 141 research/review articles, 6 chapters in books and 127 abstracts and is a reviewer for many national/international journals.
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Powder Technology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c
Pastillation: A novel technology for development of oral lipid based multiparticulate controlled release formulation Dali Shukla, Subhashis Chakraborty, Sanjay Singh, Brahmeshwar Mishra ⁎ Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi 221005, India
a r t i c l e
i n f o
Article history: Received 8 May 2010 Received in revised form 28 January 2011 Accepted 11 February 2011 Available online 18 February 2011 Keywords: Pastillation Pastilles Doxofylline Controlled release Lipid Stearic acid
a b s t r a c t A novel technique, ‘Pastillation’ to fabricate lipid based oral multiparticulate controlled release dosage forms for first time in pharmaceutical field is reported. An in-house laboratory scale device was designed to generate pastilles of doxofylline loaded stearic acid. Pastilles formed were characterized for drug content uniformity, drug release profile, morphology and contact-angle. The optimized conditions for pastillation were 1.00 cm dropping height, 20 G needle orifice and 4 °C plate temperature which produced good pastilles of uniform size (2.5– 3.0 mm) with contact angle above 90°. This multiparticulate system has very good flow property and is very uniform in size, weight and drug content and is able to sustain the drug release for a period of 24 h. This is a very simple method for producing lipid-based multi-particulate system as compared to other available techniques (melt-extrusion and freeze-pelletization) which can further be filled in capsules/sachets. The biggest advantage of this technology is that the large-scale equipment for pastillation is well-established in chemical industries. Therefore, use of this unique dosage form may open new avenue in the field of drug delivery which may even be an alternative for line extension or preparing patent non-infringing products of existing formulations. © 2011 Elsevier B.V. All rights reserved.
1. Introduction For chronic treatment, the oral controlled release drug delivery systems represent the most popular form of dosage forms. Such systems release the drug at constant rate and offer many advantages, such as nearly constant drug level at the site of action, minimum peakvalley fluctuations, reduction in dose of drug, reduced dosage frequency, avoidance of side effects, and improved patient compliance [1,2]. These formulations show a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time (sustained release), thereby ensuring sustained therapeutic action [3]. A controlled release multiparticulate system consists of multiple mini drug depots wherein the drug is either dispersed in a matrix or encapsulated in a reservoir. They are diverse in size which may vary from nano to milli scale. They are generally termed as nanoparticles, microparticles, microcapsules, pellets, minitablets and granules, which can be administered in a single dose by compressing into a dispersible tablet or filling into capsule or a sachet, in case of high dose. They can be manufactured by the agglomeration of fine powders or granules of the drug substance and excipients using appropriate processing technology and equipment. The current pharmaceutical technology has already realized the tremendous potential of controlled release multiparticulate system in ⁎ Corresponding author. Tel.: + 91 5426702748; fax: + 91 542 2368428. E-mail addresses: [email protected] (D. Shukla), [email protected] (B. Mishra). 0032-5910/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2011.02.006
terms of its flexibility in product development and therapeutic benefits to the patients in comparison to the conventional single unit dosage form. The release of drug from any modified release dosage form, of multiple strengths, changes as a function of its surface area. In case of matrix tablets of different dosage strengths, if the same blend is compressed at different weights, the change in surface area (due to change in tablet dimension) is not usually proportional to its dosage strength which results in altered drug release profile. While in case of multiparticulate system, microparticles can be divided as per the desired dosage strengths without any effect on the dimension of the individual particles. Therefore, the overall surface area of a dosage form changes proportionately with the dosage strength which does not significantly alter the drug release profile. This eases the process of scale up and scale down and reduces the extra time and cost incurred in carrying out bioequivalence studies for all other strengths. Moreover, they can also be used for delivery of incompatible drugs together or to administer drugs at different release rates in the gastrointestinal tract. When administered orally, they generally disperse uniformly in the gastrointestinal tract, maximize absorption, minimize localized side effect and reduce intra and inter subject variability [4]. Multiple unit system can also offer added advantages of prolonged gastrointestinalresistance and shorter absorption lag-time [5]. 2. Theory The present research work involves the use of wax/lipid as a major excipient in the product development. Several techniques are available in literature for the processing of waxy/lipid excipients,
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viz., melt granulation [6], melt extrusion [7], pastillation [8], melt dispersion [9], and melt solidification [10] for multi-particulate product development. Except pastillation, all other techniques have been explored for their potentials in drug delivery. Pastillation is a widely used technique in chemical, petrochemical and agrochemical industries for the solidification of dusty hazardous powders of chemicals into pastilles (hemispherical solidified units of uniform size) which eases their handling. In this process, the drops of chemical substances in molten state are deposited on a cooled stainless steel surface for rapid solidification to generate pastilles of uniform dimensions. Depending on the size of the drops and the physical properties of the melt, the drops flatten to a certain extent. The solidified droplet, therefore, has the typical pastille-like shape. The production process can easily be carried out at large scale with the help of specially designed equipments called ‘Rotoformer’ [11]. Therefore, the objective of the present work was to explore the pastillation technology for the development of immediate and controlled release multiparticulate drug delivery system. Briefly, the operating parameters for the fabrication of pastilles were optimized and then the effect of the excipients on the in vitro drug release from the dosage form was studied along with their morphological and solid state characterization. Doxofylline [12], an anti-asthmatic drug used for treatment of asthma and chronic obstructive pulmonary disorder has been used for the present study. 3. Materials and methods 3.1. Materials Doxofylline was a kind gift from Euro Drugs, Hyderabad, India. Polyethylene glycol (PEG) 400, PEG 4000 and PEG 6000 were procured from Ranbaxy Laboratories Ltd. (India). Stearic acid, colloidal silicone dioxide (Aerosil 200) and benefat were generous gifts from Witco Chemicals (Newark, NJ), Degussa (Germany) and Danisco (Denmark), respectively. All other ingredients were of analytical grade and were used as received. 3.2. Methods 3.2.1. Fabrication technology A laboratory scale device was designed in-house for producing pastilles as shown in Fig. 1 [13]. The device consisted of a glass syringe with stainless steel plunger, hypodermic needles (metallic), a metallic plate, heating coil and a 1.5 A transformer. The heating coil was wrapped on the external surface of an open ended ceramic tube and coated with a thick layer of ceramic clay for insulation. The coil was then connected with the transformer before being connected to electricity. The syringe with hypodermic needle attached was inserted into the ceramic tube. This assembly was arranged over the metallic plate with the help of a burette holder. The metallic plate was cooled with the help of ice cubes in the ice tray placed below it. The drug and other required excipients were added to the lipid/PEG melt under heating condition (140–150 °C) and were manually stirred till a clear miscible mixture was produced, which ensures homogenous distribution of drug in the matrix. The mixture was then poured into the preheated syringe and was allowed to fall drop-wise (with pressure regulation managed manually with plunger of the syringe) on to the cold plate to generate pastilles (Fig. 1 insets). After solidification, the pastilles were scrapped with the help of a sharp metallic scrapper. They were then manually filled into size ‘0’ capsules. The operating parameters for the fabrication of the pastilles were optimized using 23 factorial design. Three operating variables are needle (orifice) size (X1), dropping height (distance between the needle tip and plate surface) (X2) and temperature difference between the plate and melt (as the temperature of melt was kept constant, only temperature of plate was studied as third variable) (X3)
Fig. 1. In-house laboratory design of pastillation device [13].
each at two levels were studied on placebo batches prepared with stearic acid (Table 1). The effect of these factors was studied on the contact angle (Y1) of the pastilles as the response variable which was evaluated using MINITAB software. Table 2 shows the operating and the response variables. The optimized operating parameters obtained from the above experiments were then employed for the further preparation of batches on the basis of their flow property as presented in Table 3. 3.2.2. Contact angle measurement Contact angle of the solidified hemispherical drops i.e. pastilles was measured against solid stainless steel plate by photographic method [14]. The photographs of the pastilles were taken from the horizontal side at their contact with the plate and the snaps were then proportionally magnified and processed using Adobe Photoshop® software. The angle of contact was determined manually and confirmed mathematically using the following equation: −1
θ = 2tan
2h = d
Where h is the height of the drop from the plate and d is the diameter of the drop. Both of these dimensions can be measured from the photograph for calculating the contact angle. 3.2.3. Analytical method The standard curves of doxofylline were prepared in water, 0.1 N HCl (pH 1.2) and phosphate buffer solutions (pH 6.8) in the concentration range of 5–35 μg/ml. The solutions were analyzed by UV–VIS spectrophotometry (Hitachi U-1800). A UV visible spectrum of doxofylline showed a characteristic peak at 273 nm in all the solutions. The standard curve was plotted as drug concentration (μg/ ml) vs. absorbance plot. Curve fitting was done by linear regression analysis using Microsoft Excel program (Version 2007). Table 1 Factorial design parameters and experimental conditions. Sl No.
Factors
Low (−)
High (+)
1. 2. 3.
Needle dimensions (X1) Dropping height (X2) Temperature of plate (X3)
16 G 1 cm 4 °C
20 G 3 cm 25 °C
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4.2. Effect of operating variables on contact angle
Table 2 Formulation of the pastilles utilizing 23 factorial design. Sl. no.
Batches
X1
X2
X3
Avg. Contact angle (Y1)
1. 2. 3. 4. 5. 6. 7. 8.
A1 A2 A3 A4 A5 A6 A7 A8
16 G 16 G 16 G 16 G 20 G 20 G 20 G 20 G
1 cm 1 cm 3 cm 3 cm 1 cm 1 cm 3 cm 3 cm
4 °C 25 °C 4 °C 25 °C 4 °C 25 °C 4 °C 25 °C
121° 110° 100° 80° 120° 115° 95° 85°
3.2.3.1. Drug content uniformity. For drug content uniformity, pastilles equivalent to 10 mg of doxofylline were transferred individually into a 10 dry 25 ml volumetric flasks. 20 ml of distilled water at 75 °C was added and was sonicated in an ultrasonic water bath for 10 min while swirling occasionally. Then it was allowed to cool to room temperature. Volume was made up to the mark with distilled water. Ten milliliters of the above solution was filtered through 0.45 μm nylon filter, diluted appropriately with distilled water and was analyzed spectrophotometrically at 273 nm. Blank solution was prepared by similar treatment of placebo batches as described above in order to avoid interference due to the presence of excipients. 3.2.3.2. Drug release study. Drug release studies were carried out on six units using USP Dissolution Apparatus II (Erweka DT-6) using 500 ml of 0.1 N HCl as dissolution medium at 50 rpm and 37 ± 0.5 °C for 2 h followed by pH 6.8 phosphate buffer for next 22 h. Five milliliters of aliquots were withdrawn at predetermined intervals with replacement. The samples were filtered using 0.45 μm nylon filter and finally analyzed by UV spectrophotometer at 273 nm. 3.2.4. Scanning Electron Microscopy The morphological structure of the prepared pastilles was observed using scanning electron microscope (FEI Quantum 200E Instrument). 3.2.5. Stability study Pastilles of B-10 batch were packed in 30 ml HDPE bottles, sealed and kept at 40 °C maintained at 75% relative humidity in stability chamber (Narang Scientific Works Pvt. Ltd., New Delhi, India) for a period of 3 months as per ICH guidelines. Samples withdrawn at 1, 2 and 3 months were analyzed for drug content and drug release test. 4. Results and discussion
Contact angle of the pastilles is a measure to evaluate the spreading of a drop of melt on the plate surface before it gets solidified. The effect of various operating variables like needle size, height of needle from plate and temperature of plate on the contact angle was studied using 23 factorial design and the results are tabulated in Table 2. The primary study to optimize the operating variables was carried out using stearic acid alone (without drug). The optimized parameters were then employed for fabrication of further batches. 4.2.1. Needle size From the contour plots of contact angle vs. needle size and height of plate (Fig. 2), it was observed that at a constant plate temperature of 4 °C and variable height of plate, the contact angle of pastilles does not vary with the change in needle size. Similarly, in contour plot of contact angle vs. needle size and temperature of plate (Fig. 3), at constant height difference of 1 cm and at low temperature of plate, the contact angle is high at 16 G needle size. This effect of needle size subsides when the plate temperature is reduced gradually. Thus, it is clearly evident that needle size does not affect the contact angle remarkably and therefore, the shape of formed pastilles remains unaffected. However, the size of the pastilles increases from 2.0 ± 0.1 mm to 4.3 ± 0.2 mm with increase in the needle orifice diameter (size) from 20 G to 16 G. Further reduction in needle size beyond above range would result in difficulty in passage of melt from the needle and increase from this range can form pastilles with bigger size which cannot be filled in capsule. 4.2.2. Dropping height Effect of dropping height i.e. height difference of needle from the plate on contact angle of pastilles was also studied and was found to have an inverse relation with the contact angle as with increase in the dropping height, there was a significant decrease in the contact angle with constant plate temperature (4 °C) and needle size (Fig. 2). Similar observation was made in contour plots of contact angle vs. temperature of plate and height of needle (Fig. 4). With decrease in dropping height, the impact or force with which the drop strikes the cold surface reduces. This reduces the extent of spreading of the drop which immediately solidifies by transfer of its heat to the cold plate. The contour plots (Fig. 2 and 4) suggest that irrespective of the needle size and temperature of the plate, dropping height of ≤1.5 cm would be ideal for fabrication of pastilles with higher contact angles. Further decrease or increase in dropping height may not be possible.
4.1. Selection of excipients The excipients were selected based on the type of dosage form to be developed. For immediate release formulations, PEG was selected as the matrix former due to its water soluble nature. For controlled release formulations, stearic acid, a solid lipid (melting point ~70 °C) was selected as the matrix base due to its hydrophobic nature. PEG and benefat, a liquid lipid (at body temperature), have been used as poreformer and drug release rate modifier for the controlled release batches. Colloidal silicon dioxide was employed in some batches to improve the viscosity of the melt. Table 3 Flow property of pastilles based on their contact angle. Flow property
Contact Angle
Poor Fair Good
60–85° 85–105° 105–125°
Fig. 2. Contour plot to elaborate effect of needle size and height of needle from plate on contact angle of pastilles.
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uniformly distributed in the matrix. In addition, it also indicates that the drug does not undergo any possible degradation due to its exposure to high temperature during fabrication and is, therefore, thermostable. 4.4. Drug release study The solubility studies for the drug carried out in our laboratory indicated the maintenance of sink condition of the drug in the selected dissolution medium. Two different types of matrix forming agents (PEG and stearic acid) were used in the preparation of the pastilles. PEG based pastilles (B-1) showed immediate drug release within 45 min (Fig. 6) due to its highly hydrophilic property.
Fig. 3. Contour plot to elaborate effect of needle size and temperature of plate on contact angle of pastilles.
4.2.3. Temperature of plate At low plate temperature, sudden cooling of the drop takes place that hinders its spreading on the plate and the pastille is formed instantaneously with high contact angle. At higher plate temperature, the drop takes time to cool and solidify that provides sufficient time to drop before its spreading is stopped by solidification. Therefore, the contour plots of contact angle vs. temperature of plate and needle size and contact angle vs. temperature of plate and height of needle (Figs. 3 and 4) suggests that irrespective of the height difference and needle size, maintenance of low plate temperature (4 °C) is essential for generating pastilles of high contact angle. Further reduction in temperature can enhance contact angle by minimizing the spreading time. However, further increase in the rate of solidification may result in porous pastilles due to sudden cooling. Moreover, provision to reduce and maintain the plate temperature below 4 °C would require elaborate and sophisticated instrumentation which would add high cost to the production technology. Therefore, further change in optimized temperature may not be possible. The photographs taken during the study indicated that any contact angle greater than 90° demonstrates sufficient spherical nature of the pastilles than those with lower angles. The higher contact angle is desirable as it represents the pastilles with hemispherical shape which imparts good flow ability during large scale handling. The above observations are summarized in Table 3. Based on the above observations and the results of the contour plots, 1 cm height difference of needle from the plate and 4 °C temperature of plate were found to be the optimum parameters to generate pastilles of good contact angle. Reduced height difference results in lower impact with which the drop strikes the plate and low plate temperature will reduce the spreading time. High spreading time will give non spherical particle and will result in short contact angle followed by decrease in spherical nature of pastilles. Both these parameter assist in increasing the contact angle and hence increase the spherical nature of pastilles. 20 G needle size was selected as it produced pastilles of smaller dimension which could easily be filled into size ‘0’ capsules. Immediate release pastilles (B-1) using PEG in place of stearic acid were also prepared using the above optimized parameters and their contact angles were measured. The pastilles were very thin with large diameter and poor contact angles (b80 °C). This is due to relatively low viscosity and high spreadability of the PEG melt. Therefore, its viscosity was enhanced by addition of colloidal silicon dioxide which helped to improve its contact angle to 95°. The contact angles of pastilles of B-1 and B-10 (controlled release pastilles of stearic acid) are shown in Fig. 5.
4.4.1. Effect of release medium composition on drug release An interesting observation was made when the drug release study of the stearic acid pastilles (Batch B-2) was being carried out in pH 6.8 phosphate buffer (USP) after 2 hrs of study in 0.1 N HCl. The drug was completely released within 8 hrs (Fig. 6) and during release study the pastilles acquired a swollen disc shape which was very soft and creamy and could be easily deformed. There was a significant difference in the shape and size of pastilles before and after drug release study (Fig. 7A). The pastilles during drug release study in pH 6.8 phosphate buffer (USP) are shown in Fig. 7B. However, no change in shape, size and strength of pastilles was observed after dissolution in 0.1 N HCl. Based on the above observation, an incompatibility of the lipid with the buffer components was suspected. Therefore, the composition of 6.8 pH phosphate buffer was changed with mixed sodium buffer i.e. Na2HPO4 and NaH2PO4 which drastically changed the drug release pattern as shown in Fig. 6. The drug release was retarded to 24 h and the issues related to swelling and softening of the pastilles were also eliminated (Fig. 7C). Finally the incompatibility presumed was confirmed which may be related to the incompatibility of stearic acid with metal hydroxides [15], to form water soluble sodium salt of stearic acid. Hence, the dissolution of further batches was carried out in mixed sodium pH 6.8 buffer. The drug release from B-2 with only stearic acid in the matrix was very slow with only 24% of release in 24 h (Fig. 6). This is due to the highly hydrophobic lipid matrix and the absence of an additional pore former which together prevent the access of the aqueous medium into the inner layers. The amount of drug that was released may be the surface adsorbed drug along with the drug embedded within the matrix, which the medium could solubilize due to the pore forming ability of the water soluble drug. Here the drug release is controlled by diffusion and dissolution of the drug in the water filled pores of the matrix. In order to improve the drug release, two approaches were
4.3. Drug content uniformity The drug content values of batches B-1 and B-10 are presented in Table 4. The drug content uniformity values show that the drug is
Fig. 4. Contour plot to elaborate effect of temperature of plate and height of needle from plate on contact angle of pastilles.
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Fig. 5. Contact angle of pastilles measured by photographic method.
released in two hours after which controlled release with more than 90% drug release in 24 hrs was achieved only in case of B-4. However, the rapid drug release in the initial stage was required to be controlled which is due to faster solubilization of drug and PEG present at the surface. The remaining drug release from the pastilles is solely dependent on the mechanism of diffusion.
applied. PEG, a water soluble agent was incorporated in the lipid matrix to act as a pore former. In the second approach, benefat, a low melting lipid (liquid at body temperature) was included which could reduce the crystalline integrity of the lipid matrix and also gradually create crevices by separating from the solid matrix after melting at body temperature.
4.4.3. Effect of drug load The drug release rate increased with increase in the drug load as shown in Fig. 8. As lipid/drug ratio reduces, amount of lipid available to control the release of drug decreases, resulting in faster drug release from the matrix.
4.4.2. Effect of presence and type of poreformer Three grades of PEG (PEG 4000, PEG 6000 and PEG 400) were used as poreformer (B-3, B-4 and B-5) and their drug release profiles are presented in Fig. 6. Addition of PEGs as a poreformer was found to increase the drug release rate. As the matrix is exposed to the aqueous medium, PEG and the drug on the surface starts to dissolve which provides space for the aqueous medium to gain access to the lower lying layers. This continuous process generates pores with increasing network within the matrix. The release rate was fastest with PEG 6000 than PEG 4000 and slowest with PEG 400. This pattern of release rate may be attributed to their physical state, molecular weight and hydrophilicity. As the molecular weight of PEG increases, their melting point increases. PEG 400 being liquid in nature forms channels faster than other two PEGs which are solid at 37 °C and therefore, takes time to solubilize. However, in the liquid state, size of the pores formed is relatively smaller during solidification of the melt. PEG 400 being in the liquid state is homogenously distributed throughout the matrix. In case of solid PEGs, they form bigger pores due to their significantly higher molecular weight. This is exemplified by the faster drug release rate of batch B-4 than batch B-3 as molecular weight of PEG 6000 is higher than PEG 4000 which results in comparatively bigger channels. Overall, about ≤ 30% of drug was
4.4.4. Type of lipid combination Benefat is a mixture of triacylglycerols containing short chain (acetic, propionic, and/or butyric acids) and long chain (stearic acid, canola and soybean oil) fatty acids with stearic acid as the predominant long chain fatty acid (58 to 67 g per 100 g triacylglycerol) [16]. It is semi-solid at room temperature and melts to a clear liquid at body temperature. The drug release profiles of batches with benefat (Batches B-8, B-9 and B-10) are shown in Fig. 9. In batch B-8, the release profile was almost similar to that of batch B-3 with a slight reduction in initial release, as expected due to the hydrophobic nature of benefat. At the same time, a reduction in the pastille strength was observed due to the presence of excess amount of liquid lipid which interfered with their crystalline integrity. The batches failed to withstand the agitation and therefore, could not maintain their integrity in the medium during the dissolution study. Pastilles with reduced amount of benefat (Batch B-9) or without
Table 4 Formulation composition of the prepared batches using pastillation technique. Composition
DOX Stearic acid Benefat PEG 4000 PEG 6000 PEG 400 Colloidal slilcon dioxide Drug content Uniformity(%)
mg/batch B-1
B-2
B-3
500
500 2000 – – – –
500 2000 – 300 – –
2000
75 100.56 ± 0.93
B-4 500 2000 – – 300 –
B-5
B-6
B-7
B-8
B-9
B-10
500 2000 – – – 300
300 2000 – 300 – –
400 2000 – 300 – –
500 1700 300 – – –
500 1700 150 – – –
500 1700 75 – – – 98.89 ± 1.23
70
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Fig. 8. Drug release profiles showing effect of drug load on drug release of pastilles. Fig. 6. Drug release profiles showing effect of pore former on drug release behavior of pastilles.
benefat (Batch B-1) were found to have sufficient strength to withstand the agitation of the drug release condition. The initial drug release rate was controlled with a linear profile (R2 = 0.985) achieved in case of batch B-10.
faster solidification rate and higher viscosity of the melt. The drop with high viscosity does not get time to spread too much due to faster solidification and low spreadability. The magnified view of B10 (Fig. 10D) showed presence of pores on the upper surface probably formed because of the high rate of solidification which prevents the proper spreading of the melt. 4.6. Stability study
4.5. Scanning electron microscopy The photomicrograph of pastille of B-1 showed a very smooth and uniform texture with a round structure (Fig. 10A). Another picture at higher magnification (Fig. 10B) revealed its highly crystalline and porous matrix. The high porosity and high solubility of PEG in water are the major reasons for fast drug release from the PEG based matrix. On the other hand, pastille of B-10 also has round structure (Fig. 10C), but is smaller in size than B-1 pastille due to its
On comparing the stability data of the stored samples with that of the initial samples, it was observed that neither the physical appearance nor the drug release profiles of the stored samples were influenced by the storage condition (Fig. 11). No change in drug content of the formulation was found (1 M-98.66%, 2 M-97.12%, 3 M96.46%). This indicates that the lipid excipient of the formulation is physically stable and capable of withstanding the environmental fluctuations.
Fig. 7. Incompatibility of drug carrier with composition of dissolution medium (A) pastilles before and after dissolution in pH 6.8 phosphate buffer (USP), (B) pastilles during drug release study in pH 6.8 phosphate buffer (USP), (C) pastilles during drug release study in pH 6.8 mixed sodium phosphate buffer.
D. Shukla et al. / Powder Technology 209 (2011) 65–72
Fig. 9. Drug release profiles showing effect of lipid composition and type of pH 6.8 phosphate buffer media on drug release behavior of pastilles.
5. Limitations of the technology This technology is particularly applicable to carriers of low melting points which melt and are capable of re-solidification at room tem-
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Fig. 11. Comparison of drug release profiles of initial and stability samples of final batch.
perature i.e. lipids, waxes and macrogols. In addition, as the fabrication process involves the use of temperature for melting the excipients, the drug being incorporated should not be degraded during processing, i.e. it must be thermostable in the processing temperature range.
Fig. 10. Morphological study of pastilles by Scanning Electron Microscopy (A) Batch B1 (B) Batch B1 at higher magnification (C) Batch B10 (D) Batch B10 at higher magnification.
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6. Conclusion Pastillation technology was successfully used to fabricate the controlled release pastilles of uniform size and with 24 h drug release controlling ability using lipids as a carrier and release rate modifier. This technology is very simple for producing lipid-based multiparticulate system, as compared to the other available techniques (melt-extrusion and freeze-pelletization), which can further be filled into capsules/sachets as the final dosage form. 7. Future perspective The present study involves the development of a new dosage form of lipid based multiparticulate system for controlled drug delivery by oral route using pastillation. A major advantage with this formulation is that it can be easily scaled-up with the existing pastillation equipment that is well established in the chemical industry. Therefore, this dosage form with a unique dimension may open a new avenue in the field of drug delivery which may even be an option for line extension or preparing patent non-infringing formulations of existing drug products. Use of lipids as the major excipient would also be helpful in reducing the dosage of the drug, especially poorly water soluble drugs [17]. Furthermore, the immediate release pastilles prepared in the present study, if amalgamated with appropriate taste and color, would add as a new item in the product basket of dosage forms for oral delivery. Acknowledgment The first author gratefully acknowledges the financial assistance provided by Indian Council of Medical Research, New Delhi, India, in the form of Senior Research Fellowship to support this research work. References [1] A.R. Gennaro (Ed.), Remington: The Science and Practice of Pharmacy, 20th ed, Lippincott, Williams & Wilkins, USA, 2000. [2] T. Bussemer, I. Otto, R. Bodmeier, Pulsatile drug delivery systems, Crit. Rev. Ther. Drug Carrier Syst. 18 (2001) 433–458. [3] N.G. Das, S.K. Das, Controlled release of oral dosage forms, Formulation, Fill and Finish, 2003, pp. 10–16www.pharmtech.com. [4] H. Bechgaard, G.H. Nielsen, Controlled-release multiple-units and single-unit doses — a literature review, Drug Dev. Ind. Pharm. 4 (1978) 53–67. [5] Y. Ito, H. Arai, K. Uchino, K. Iwasaki, N. Shibata, K. Takada, Effect of adsorbents on the absorption of lansoprazole with surfactant, Int. J. Pharm. 289 (2005) 69–77. [6] T. Schaefer, P. Holm, H.G. Kristensen, Melt granulation in a laboratory scale high shear mixer, Drug Dev. Ind. Pharm. 16 (1990) 1249–1277. [7] J.L. White, W. Szdlowski, K. Min, M.H. Kim, Twin screw extruders: development of technology analysis of flow, Adv. Polym. Technol. 7 (1987) 295–332. [8] J.W. Kim, J. Ulrich, Prediction of degree of deformation and crystallization time of molten droplets in pastillation process, Int. J. Pharm. 257 (2003) 205–215. [9] C.M. Adeyeye, J.C. Price, Development and evaluation of sustained release ibuprofen-wax microspheres. I. Effect of formulation variables on physical characteristics, Pharm. Res. 8 (1991) 1377–1383. [10] A.R. Paradkar, M. Maheshwari, A.R. Ketkar, B. Chauhan, Preparation and evaluation of ibuprofen beads by melt solidification technique, Int. J. Pharm. 255 (2003) 33–42. [11] http://www.processsystems.sandvik.com/. [12] S. Chakraborty, D. Shukla, B. Mishra, S. Singh, Lipid — an emerging platform for oral delivery of drugs with poor bioavailability, Eur. J. Pharm. Biopharm. 73 (2009) 1–15. [13] D. Shukla, S. Chakraborty, S. Singh, B. Mishra, Lipid based oral multiparticulate formulations — advantages, technological advances and industrial applications, Expert Opin. Drug Deliv. 8 (2011) 207–224.
[14] W. Gutowski, Thermodynamics of adhesion, in: Lieng-Huang Lee (Ed.), Fundamentals of adhesion, Plenum Publishing Corporation, New York, 1991, pp. 87–136. [15] R. Mahalingam, X. Li, B.R. Jasti, Semisolid dosages: ointments, creams and gels, in: S.C. Gad (Ed.), Pharmaceutical Manufacturing Handbook: Production and Processes, John Wiley and Sons, Inc, New Jersey, 2008, pp. 267–312. [16] M.T. Tarrago-Trani, K.M. Phillips, L.E. Lemar, J.M. Holden, New and existing oils and fats used in products with reduced trans-fatty acid content, J. Am. Diet. Assoc. 106 (2006) 867–880. [17] D. Shukla, S. Chakraborty, S. Singh, B. Mishra, Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease, Expert Opin. Pharmacother. 10 (2009) 2343–2356.
Dali Shukla is a Senior Research Fellow in Banaras Hindu University. She has an experience in formulation research development for 3 years in Lupin Research Park and Sandoz Pvt. Ltd, India. She has expertise in technology transfer of several immediate release products and is well versed in granulation, compression, coating and capsule filling. Her current area of research is lipid based oral multiparticulate formulations. She has 15 publications and has presented/co-authored 9 research works in national/ international journals/conferences. She has been awarded International Travel Fellowship of DBT, New Delhi and CCSTDS, Chennai, for presenting her research work in the Australasian Pharmaceutical Science Association conference, Australia in 2009. She is recipient of the prestigious AU-CBT Excellence Award of Biotech Research Society, India.
Subhashis Chakraborty, a Senior Research Fellow, Banaras Hindu University has an industrial research experience in formulation development for 3 years in Lupin Research Park, and Sandoz Pvt. Ltd. He has expertise in granulation, tablet compression, coating, fluidized bed pelletization and extrusion–spheronization. His current area of research is lipid based oral nanoparticulate formulations. He has 15 publications in international journals and has reviewed for many journals. He has presented/co-authored 11 research works in national/international conferences. He has been awarded International Travel Fellowship of DST, New Delhi, for presenting his research work in Australasian Pharmaceutical Science Association Conference, Australia in 2009.
Sanjay Singh has a research career span of nearly 20 years in the development of novel drug delivery systems for improved therapeutic performance and patient compliance. He has authored/co-authored 65 research/review articles in national/international journals, presented 44 papers in conferences and published one chapter in a book. He is a reviewer of many national/international journals. His current research interest involves the development and pharmacological evaluation of nanomedicines. He has projects of approximately worth Rs. 70 lacs. He is also a reviewer of various national and international journals and research projects. He has supervised 2 PhD and 19 M. Pharm. students till date.
B. Mishra has major scientific contributions in areas the of drug delivery, bioavailability enhancement, pharmacokinetic and pharmacological evaluation. He has developed stomach targeted floating formulations of clarithromycin and amoxicillin for treatment of Helicobacter pylori induced diseases and various other drug delivery systems for effective and safe management of pain, inflammation, diabetes and amoebic colitis. His current area of interest is development of multiparticulate formulations for controlled and targeted delivery. He has supervised 7 students for Ph.D. and 33 students for M. Pharm., published 141 research/review articles, 6 chapters in books and 127 abstracts and is a reviewer for many national/international journals.