Stabilization of Low Glass Transition Temperature Indomethacin Formulations: Impact of Polymer-Type and Its Concentration

RINA J. CHOKSHI,1,2 NAVNIT H. SHAH,2 HARPREET K. SANDHU,2 AHMAD W. MALICK,2 HOSSEIN ZIA1
1 2

Applied Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island Pharmaceutical & Analytical Research & Development, Hoffmann-La Roche, Nutley, New Jersey

Received 19 March 2007; revised 22 June 2007; accepted 6 July 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21174

ABSTRACT: The objectives of this study were to formulate and stabilize amorphous formulation of low Tg drug (Indomethacin, INM) with selected polymers and compare these formulations based on solubility and dissolution rate studies. Eudragit EPO (EPO), Polyvinylpyrrolidonevinyl acetate copolymer (PVPVA), and Polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers. The melt extrudates were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), intrinsic dissolution rate and solubility studies. The formation of single-phase amorphous form was conrmed by DSC and PXRD. The melt extrudates showed a higher intrinsic dissolution rate (IDR), and solubility compared to the pure drug. The amorphous drug in solid solutions with EPO, PVPVA, and PVPK30 showed tendency to revert back to crystalline form. However, the rate of reversion was dependent on the nature and concentration of the polymer. The solid solution with high ratio of EPO provided superior stabilization of the amorphous INM from crystallization. The stability of the amorphous form of INM could not be related to the glass transition temperature of the formulation as the mechanism of stabilization with EPO appears to be molecular interaction rather than immobilization. The presence of specic molecular interactions between INM and EPO was also shown by the antiplasticization effect. 2007 Wiley-Liss,
Inc. and the American Pharmacists Association J Pharm Sci 97:22862298, 2008

Keywords: crystallinity; dissolution rate; extrusion; glass transition; polymers; solid dispersion; solid solutions; stability; thermal analysis; X-ray powder diffractometry

INTRODUCTION
The bioavailability of orally administered drugs mainly depends on solubility and permeability. Due to the advent of high throughput screening (HTS) in the drug discovery process, the resultant compounds are often high molecular mass, high lipophilicity, and poor water solubility drugs.1 Formulation scientists have attempted to address
Correspondence to: R.J. Chokshi (Telephone: 845-602-7968; Fax: 845-602-5529; E-mail: chokshr@wyeth.com)
Journal of Pharmaceutical Sciences, Vol. 97, 22862298 (2008) 2007 Wiley-Liss, Inc. and the American Pharmacists Association

solubility issues by various pharmaceutical interventions.25 In this study, a solid solution approach was considered to improve the dissolution rate of a poorly water-soluble and low glass transition temperature (Tg) model drug Indomethacin (INM). The most cited methods in the literature to formulate solid solutions are melting of excipients or fusion method,6 embedding of drug by means of spray drying,7 coevaporation, coprecipitation,8 freeze-drying,9 and roll-mixing or comilling.10,11 For the purpose of this discussion, the drug/ polymer system can be dened as solid solution

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when the drug is dissolved at a molecular level, that is, when the drug forms one phase system with polymer. In order to qualify as solid solution, the drug/polymer system should satisfy the following criteria: (a) The mixtures of drug and polymer should show single glass transition temperature. (b) The drug should be present in amorphous form.12,13 The improvement in bioavailability with solid solution is primarily improvement in the dissolution rates and solubility due to the presence of high-energy amorphous form.14 Comparing crystalline and amorphous solids, the three-dimensional long range order that normally exists in a crystalline material does not exist in the amorphous state. In other words, the amorphous solids have macroscopic properties of a solid with the microscopic structure of a liquid. By the virtue of high internal energy, the amorphous solids possess enhanced thermodynamic properties, molecular motions, and chemical reactivity as compared to crystalline solids.14 Since molecules in the amorphous state are thermodynamically metastable as compared to crystalline state, the potential for crystallization during processing and storage is always present. Hancock et al. have published extensive information regarding the factors affecting stabilization of amorphous state.1416 The critical factors affecting stability of amorphous state are the Tg, hygroscopicity, purity and storage conditions. The presence of moisture can show plasticization effect and lower the Tg, which can increase the probability of conversion of amorphous state to crystalline state. The Tg of the drug can be increased by adding polymers with high Tg values. In drug/polymer system, the stability of the amorphous form primarily depends on criteria such as drug and polymer interaction, viscosity of polymer, and glass transition temperature of the mixture.1719 The literature has shown that higher glass transition temperature and higher viscosity of polymers usually show superior stability for the amorphous drug.14,15 The specic interactions between drug and polymer are important considerations for stabilization of the amorphous formulation. Therefore the evaluation and selection of polymer is a key factor in developing solid solution. For this study the hot-melt extrusion technology was utilized to prepare solid solution of the poorly
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water-soluble model drug. This technology employs application of high shear and high temperature to formulate solid solutions. This technology has many advantages over traditional processing techniques such as spray drying or coevaporation which involves organic solvents. Some of the important advantages are solvent free continuous process and relatively smooth scale-up. The primary objective of this study was to obtain stable solid solution of poorly water soluble and low Tg model drug with water insoluble/ionic polymer and water soluble/non ionic polymers. The secondary objective was to evaluate performance attributes of solid solutions as a function of polymer-type and concentrations. INM was selected as the poorly water-soluble model drug and Eudragit EPO (EPO), polyvinylpyrrlidonevinyl acetate (PVPVA), and polyvinylpyrrolidone K30 (PVPK30) were selected as hydrophilic polymers.

MATERIALS AND METHODS

Materials INM was purchased from Ria International LLC. (Whippany, NJ). EPO was purchased from Rohm America (Degussa Corporation, Parsippany, NJ). PVPVA (Plasdone S630) was supplied by ISP Corporation (Wayne, NJ) and PVP K30 was purchased from BASF Corporation (Florham Park, NJ). All other chemicals used were of analytical grade. The physicochemical properties of the drug and polymers used in the study are tabulated in Table 1.

Methods Preparation of Physical Mixtures The drug and polymers were passed through a 60mesh screen and mixed thoroughly in a mortar with pestle. These mixtures were further mixed in turbula mixer for additional 20 min. The different ratios of drug to polymer prepared for the study were: 30:70, 50:50, and 70:30. Preparation of Melt Extrudates Hot-melt extrusion was performed in Micro-18 twin screw corotating extruder (American Leistritz Extruder Corporation, Somerville, NJ). The extrusion barrel was divided in eight temperature zones. The extrusion temperatures varied for
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Table 1. PhysicoChemical Properties of the Drug and Polymers PhysicoChemical Properties Aqueous solubility Molecular mass Tg and melting point XRD pattern INM Poorly soluble ($0.004 mg/mL) 357.81 g/mol 1658C and Tg 428C Crystalline Eudragit EPO Soluble at pH<5 150000 g/mol Tg 458C Amorphous PVPVA Water soluble 50000 g/mol Tg 1108C Amorphous PVPK30 Water soluble 50000 g/mol Tg 1618C Amorphous

various polymers although they were kept above Tg of the polymers. The extrusion screw speed was kept at 5560 rpm and K-Tron-automated gravimetric feeder was used to feed the material in melt extruder at 56 g/min. The process parameters such as motor load and melt pressures were recorded for each formulation (Tab. 2). INM was extruded with various polymers such as EPO, PVPVA, and PVPK30 as binary mixtures at drug to polymer ratios of 70:30, 50:50, and 30:70. Milling of Hot-Melt Extrudates The resultant extrudates were cooled on air conveyor belt and milled using FitzMill1 Comminutor (South Plaineld, NJ). The milling process consisted of two passes, rst pass with a sieve # 2 (sieve size 0.065 inch, coarse milling) and second pass with a sieve # 1 (sieve size 0.033 inch, ne milling). Thermal Analysis Thermal analysis was carried out using a SII 5200 DSC (TA Instruments, Newcastle, DE), equipped with a liquid nitrogen-cooling accessory. Samples (510 mg) were prepared in sealed pans. The samples were scanned at a heating rate of 108C/ min. The data were treated mathematically using the DSC 5200 Disk Station Analysis program.

Powder X-Ray Diffraction (PXRD) The various samples were analyzed by PXRD (Scintag Inc., Cupertino, CA) using Cu Ka radiation to determine the crystalline or amorphous state of the drug in the melt extrudate. The PXRD patterns were collected in the angular range of 1 < 2u < 408 in step scan mode (step width 0.028, scan rate 1 deg/min). FT-IR Spectroscopy These studies were helpful in elucidating the interaction between the drug and polymers. IR absorbance spectra were obtained using Perkin Elmer, Spectrum GX series spectrometer equipped with DTGS detector. The test solid (0.81%) was mixed with KBr and analyzed using the diffuse reectance method. Fifty scans were collected for each sample at a resolution of 4 cm1 over wave number region 4000400 cm1. Solubility Studies The solubility of the various melt extrudates were performed in simulated gastric uid (SGF) at pH 1.5 (SGF) and simulated intestinal uid at pH 6.8 (SIF). An excess amount of formulation was mixed with 20 mL of dissolution medium and was shaken at ambient conditions in a mechanical

Table 2. Critical Process Parameters of HME Process for Various Formulations Formulations of Drug:Polymer 70:30 50:50 30:70 70:30 50:50 30:70 70:30 50:50 30:70 Barrel Temperatures Feed-Extrusion 18 Barrels 80, 110, 115, 120, 120, 120, 125, 125

Polymers EPO

Motor Load in % 83.3 2.6 91.6 1.7 95.3 1.3 31.3 1.7 33.9 3.1 83 1.8 33.4 1.5 38.6 1.7 83.6 4.2

Melt Pressure in psi 14.7 1.8 85.1 3.1 146.4 4.6 15.5 0.5 41.3 0.6 72.5 2.4 10.3 1.1 73.4 5.2 649.3 6.4

PVPVA

85, 110, 125, 125, 130, 130, 135, 135

PVPK30

100, 125 125, 130, 140, 145, 150, 150

Feed rate 56 g/min. Screw speed 5560 rpm.

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shaker. The solubility of drug was measured after 24 and 72 h. The UV spectroscopy was used to determine the solubility of the drug in dissolution medium at 316 nm. Dissolution Studies Intrinsic dissolution or constant surface area dissolution was studied using a Woods apparatus. About 100 mg of the powder was compressed in Woods apparatus die ($diameter 0.8 cm) using a Carver Press at 4000 psi pressure and a dwell time of 10 s. Dissolution was performed using a USP Dissolution Apparatus II (Distek Inc., North Brunswick, NJ) connected to HP UVVis spectrophotometer Model 8452 (Hewlett-Packard Co., Palo Alto, CA) with a 900 mL of SGF with pH 1.5 and simulated intestine uid (SIF) with pH 6.8 as dissolution mediums at 378C and a paddle speed of 50 rpm. Stability Studies The accelerated stability studies were conducted to determine the effect of high temperature and humidity on the physical stability of the drug in various formulations. The hot-melt extrudates with various polymers and the drug as is were stored at 408C/75% RH for 3 months in open glass vials. For comparison purpose these formulations were stored at controlled room temperature in closed vials. Various analytical methods such as DSC, PXRD, and intrinsic dissolution studies were used to access the stability of the formulation.

melt pressure were dependent on molecular mass and viscosity of polymer and drug polymer interactions. The binary mixture with drug and polymer ratio 30:70 showed higher motor load and melt pressure as compared to 50:50 and 70:30. Increasing the concentration of drug decreased the motor load and melt pressure, indicating a reduction in viscosity of the polymer due to solubilization of the drug. Since the molecular mass of EPO is higher as compared to PVPVA and PVPK30 (Tab. 1), formulations with EPO showed higher motor load. Thermal Analysis DSC was carried out to determine glass transition temperature of the melt extrudates. The crystalline INM showed an endotherm at 1658C and amorphous INM after heating and quenching showed a glass transition temperature (Tg) at 428C. EPO, PVPVA, and PVPK30 are amorphous in nature and showed Tg at 45, 109, and 1628C, respectively. In case of melt extrudates with EPO, a single Tg was observed suggesting the formation of solid solution that is one phase system. However, the Tg of melt extrudate increased as a function of drug concentration suggesting an antiplasticization effect due to intermolecular interaction between INM and EPO21 (Fig. 1). A similar effect was observed with regards to the effect of temperature on viscosity for INM and EPO system.22 Since EPO is cationic and INM is a weak acid, a potential for ionic interaction exists between them23, however, no experimental evidence could be obtained to conrm this hypothesis. In case of melt extrudates with PVPVA and PVP K30, a single Tg was observed indicating formation of solid solution that is drug and polymers were present in a one phase system. INM acted as plasticizer for PVPVA and PVP K30 and the Tg of melt extrudates were in between the pure drug and pure polymers (Fig. 1).

RESULTS AND DISCUSSION

Evaluation of HME Process The critical process parameters for various formulations are listed in Table 2. The extrusion temperature gradient, feed rate, and screw speed were input parameters and motor load and melt pressures were output parameters. The extrusion temperatures were dependent on glass transition temperatures (Tg) of the polymers and the temperature gradient across the barrel were kept constant for each drug/polymer systems. The extrusion temperatures were below the melting point of INM. Feed rate and screw speed were kept constant at 56 g/min and 5560 rpm, respectively, for all formulations to ensure a constant ll and shear in the extruder.20 Thus, motor load and
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Powder X-ray Diffraction Studies Powder X-ray diffraction (PXRD) is an essential technique in studying the crystalline or amorphous nature of the drug in solid solutions. The PXRD for INM showed distinctive peaks at 10, 12, 13, 17, 19, 20, 21, 22, 23, 24, 27, and 29 degrees indicating its crystalline nature as shown in Figure 2. This gure also compares the correJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008

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Based on thermal analysis and PXRD, it was conrmed that INM formed one phase system with these polymers and drug was present in high-energy amorphous form.

FT-IR Studies FT-IR studies were performed on various melt extrudates to elucidate interactions between INM and polymer and to conrm the crystalline or amorphous nature of drug in the melt extrudate. The crystalline INM showed strong C O bond stretch at 1718 and 1692 cm1.When the INM was converted to the amorphous form the C O bond stretch shifted to 1709 and 1683 cm1. The FT-IR studies of melt extrudates with EPO, PVPVA, and PVPK30 showed the presence of amorphous INM; however, there was no evidence of interaction between drug and polymers.

Figure 1. Phase diagram of melt extrudates with EPO, PVPVA, and PVPK30. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]

sponding PXRD of the INM, physical mixture, and melt extrudate with EPO. The presence of drug peaks in PXRD of physical mixture indicated crystalline nature of the drug while absence of peaks in melt extrudate suggested amorphous nature of the drug in the melt extrudate. Melt extrudates with various ratios of drug/ EPO, drug/PVPVA, and drug/PVPK30 showed the absence of drug peaks, which indicated that INM was present in an amorphous form (Fig. 3). This observation further supported thermal analysis in conrming the formation of solid solution of the drug with these polymers.

Solubility Studies INM is a weak acid (pKa 4.5) and shows pHdependent solubility. The INM solubility increases with the increase in pH.22 The EPO is cationic polymer and is soluble at pH less than 4 but permeable at higher pH. The PVPVA and PVPK30 are nonionic polymers and has pHindependent solubility. Therefore the solubility studies were performed in two different pH conditions: SGF pH 1.5 and phosphate buffer SIF pH 6.2. The drug solubility from the various formulations in SGF and SIF are shown in Table 3. The pure drug has negligible solubility in SGF, however, shows a solubility of 1.06 mg/mL in SIF. The melt extrudates with EPO showed increased solubility in SGF. The increase in solubility was dependent on EPO concentration. The higher amount of EPO in the melt extrudate increased the drug solubility in SGF. The melt extrudate with drug to EPO ratio of 30:70 showed signicant increase in solubility compared to pure drug and 320-fold increase in solubility compared to corresponding physical mixture after 72 h (Tab. 3). The melt extrudates with drug to EPO ratio of 70:30 and 50:50 showed lower solubility at 72 h as compared to 24 h. As shown in Figure 4 the decrease in solubility may be attributed to the partial conversion of amorphous drug to crystalline form in SGF at 72 h. However, there was no change in solubility for 30:70 formulation even after 72 hours suggested that amorphous drug
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Figure 2. PXRD comparing INM, physical mixture, and melt extrudate with EPO (drug:polymer 50:50). [Color gure can be seen in the online version of this article, available on the website, www.interscience. wiley.com.]
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Table 3. Solubility of Various Formulations in SGF and SIF after 24 and 72 h Solubility in SGF in mg/mL Formulation Indomethacin Formulation with PM 70:30 PM 50:50 PM 30:70 HME 70:30 HME 50:50 HME 30:70 Formulation with (drug:polymer) PM 70:30 PM 50:50 PM 30:70 HME 70:30 HME 50:50 HME 30:70 Formulation with (drug:polymer) PM 70:30 PM 50:50 PM 30:70 HME 70:30 HME 50:50 HME 30:70 24 h 72 h Solubility in SIF in mg/mL 24 h 72 h

N/A N/A 1.06 1.0 EPO, PM, and HME (drug:polymer) 0.05 0.02 0.45 0.54 0.07 0.04 0.36 0.47 4.71 0.12 0.18 0.19 0.21 0.15 2.74 2.68 6.52 0.14 0.77 1.99 41.72 38.31 0.26 0.22 PVPVA, PM, and HME 0.00 0.00 1.77 0.00 0.00 2.37 0.01 0.00 2.51 0.00 0.03 14.27 0.01 0.01 33.22 0.01 0.02 8.87 PVPK30, PM, and HME 0.00 0.00 0.01 0.00 0.04 0.1 0.00 0.00 0.00 0.02 0.05 0.29 1.35 1.65 1.55 38.55 34.31 19.39 1.53 2.16 2.70 3.91 5.44 6.37

Figure 3. PXRD of various melt extrudates with (a) EPO (b) PVPVA (c) PVPK30. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]

1.25 1.54 1.61 4.28 4.00 4.98

N/A, could not be detected; PM, physical mixture; HME, hot-melt extrudate.

showed superior stability at high polymer concentration. As shown in Table 3, the improvement of the drug solubility in melt extrudate with INM/EPO in SIF was signicantly lower as compared to SGF. In addition, the increase in solubility was inversely related to polymer concentration. This can be attributed to the poor solubility of EPO and good solubility of the drug in SIF rather than the instability of the amorphous form. This was further conrmed by PXRD. The melt extrudates with PVPVA and PVPK30 did not show any signicant improvement in solubility in SGF indicating the instability of amorphous form. The conversion of amorphous form to crystalline form was conrmed by PXRD of excess solids after 24 and 72 h (Fig. 5). The melt extrudates with PVPVA and PVPK30 showed signicant increase in solubility in SIF at 24 h (from 20-folds to 30-folds). However, the solubility decreased at 72 h suggesting conversion
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of the amorphous form to crystalline form. The observed increase in solubility was inversely related to polymer concentration at 24 h, which was attributed to the high viscosity at high

Figure 4. PXRD of the various melt extrudate with EPO in SGF after 72 h. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]
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The high polymer concentration (EPO) helped in stabilizing amorphous form of the drug even after 72 h during stability studies. On the contrary PVPVA and PVPK30 did not show any signicant increase in solubility in SGF but these formulations showed improved solubility in SIF. However, the improved solubility could not be maintained at 72 h. Intrinsic Dissolution Studies The intrinsic dissolution rates (IDR) of drug and various formulations in SGF and SIF are summarized in Table 4. The IDR of the drug was 0.001 mg /cm2 min in SGF, however, the dissolution rate increased by 40-folds in SIF. The intrinsic dissolution proles for melt extrudate containing the drug and EPO are shown in Figure 6. The thermal and PXRD analysis of melt extrudate had shown that the drug is present in amorphous form. Correspondingly, the IDR of melt extrudates was found to be signicantly higher as compared to the pure drug and the physical mixture in SGF. Furthermore, the IDR were found to be dependent on polymer concentration. The highest IDR was observed with drug/EPO ratio of 50:50. The dissolution rate increased by 2000-folds as compared to the pure

Figure 5. PXRD of the various melt extrudate with PVPVA in SGF after 72 h. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]

polymer concentration. Despite the conversion to crystalline form, the equilibrium solubility from melt extrudates was higher than the pure drug or the corresponding physical mixtures. This may be related to the stabilization of dissolved drug by the polymer in the solution. In summary, the melt extrudate with EPO showed signicant increase in solubility in SGF, however, marginal increase was observed in SIF.

Table 4. Intrinsic Dissolution Rates for Various Formulations in SGF and SIF Formulations IDR in mg/cm2 min in SGF IDR in mg/cm2 min in SIF 0.04 0.01 0.08 0.004 0.05 0.002 0.02 0.001 0.01 0.002 0.01 0.001 0.01 0.002 0.08 0.003 0.17 0.01 0.27 0.01 0.94 0.16 1.13 0.19 0.65 0.09 0.08 0.004 0.14 0.01 0.26 0.06 1.04 0.05 0.91 0.07 0.30 0.01

INM 0.001 0.0005 Formulation with EPO, PM, and HME (drug:polymer) PM 70:30 0.01 0.001 PM 50:50 0.06 0.01 PM 30:70 0.04 0.01 HME 70:30 1.47 0.04 HME 50:50 2.21 0.13 HME 30:70 1.79 0.21 Formulation with PVPVA, PM, and HME (drug:polymer) PM 70:30 0.01 0.001 PM 50:50 0.01 0.001 PM 30:70 0.01 0.003 HME 70:30 0.01 0.001 HME 50:50 0.01 0.002 HME 30:70 0.01 0.001 Formulation with PVPK30, PM, and HME (drug:polymer) PM 70:30 0.003 0.001 PM 50:50 0.01 0.003 PM 30:70 0.01 0.001 HME 70:30 0.01 0.002 HME 50:50 0.01 0.003 HME 30:70 0.01 0.003
PM, physical mixture; HME, hot-melt extrudate.
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Figure 6. Dissolution prole comparing various compositions of melt extrudates with EPO in SGF. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]

drug and 35-folds as compared to the corresponding physical mixture (Tab. 4). The increase in IDR was directly related to the EPO concentration up to 50:50. The IDR was slightly lowered at higher polymer concentration (70%), which could be attributed to high polymer viscosity and thus lower drug diffusivity (Tab. 4 and Fig. 6). The dissolution proles of melt extrudates showed tendency to revert back to crystalline form in SGF. This nding is consistent with literature data where metastable amorphous form has been shown to crystallize out from supersaturated solution. For the drug/EPO formulations, the conversion to crystalline form were directly related to the polymer concentration. The time to reversion increased with increase in the polymer concentration. In spite of the reversion, the equilibrium solubility of the drug in dissolution medium was higher than the pure crystalline form.
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The IDR of drug/EPO melt extrudate in SIF were lower than the pure drug, despite the higher drug solubility of the drug in SIF (Tab. 4). A decrease in IDR from melt extrudate indicates that the drug is bound to polymer and the low dissolution rate is due to the insolubility of the polymer in SIF and not the physical instability of INM. The melt extrudates with PVPVA and PVPK30 did not show signicant improvement in IDR as compared to the pure drug and the corresponding physical mixture in SGF (Tab. 4). The low dissolution rate was attributed to the conversion of amorphous drug to stable crystalline form during the dissolution. The melt extrudates with PVPVA and PVPK30 showed an improved IDR as compared to pure drug and corresponding physical mixtures in SIF. In the case of PVPVA, the melt extrudate at the ratio of 50:50 showed 28-folds higher IDR as compared to the pure drug and 7-folds higher as compared to
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Figure 7. Dissolution prole comparing various compositions of melt extrudates with PVPVA in SIF. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]

the corresponding physical mixture (Tab. 4). In the case of PVPK30, the melt extrudate at the ratio of 50:50 showed 23 fold higher IDR as compared to the pure drug and 7 fold higher as compared to corresponding physical mixture (Tab. 4). The increasing polymer concentration showed decrease

in IDR (Figs. 7 and 8). Despite the similarity in PVPK30 and PVPVA system, the different trends were observed for IDR as a function of polymer concentration. The PVPVA system showed an increase in IDR up to 50% polymer concentration followed by a decrease in IDR at 70% polymer

Figure 8. Dissolution prole comparing various compositions of melt extrudates with PVPK30 in SIF. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]
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Table 5. Glass Transition Temperature Comparing Initial and 3 Months 408C/75% RH Formulations Tg in 8C Initial Tg in 8C 3 Months 408C/75% RH

Formulations Formulation with HME 70:30 HME 50:50 HME 30:70 Formulation with HME 70:30 HME 50:50 HME 30:70 Formulation with HME 70:30 HME 50:50 HME 30:70

Figure 9. PXRD of melt extrudates with EPO in SIF. [Color gure can be seen in the online version of this article, available on the website, www.interscience. wiley.com.]

EPO HME (drug:polymer) 62.3 0.3 63.6 0.2 55.3 0.7 57.2 0.5 45.9 0.5 47.8 0.6 PVPVA HME (drug:polymer) 59.4 0.7 58.8 0.4 71.1 0.3 69.7 0.3 80.8 0.9 76.5 0.6 PVPK30 HME (drug:polymer) 74.8 0.3 72.9 0.7 92.9 0.6 90.2 0.9 115.2 0.8 110.5 0.8

HME, hot-melt extrudate.

concentration. However, in the case of PVPK30, IDR decreased as function of polymer concentration from 30% to 70 %. This can be attributed to higher glass transition temperature and thus lower drug mobility of the drug in PVPK30 system as opposed to PVPVA system. To conrm the physical stability of the INM during dissolution, a small amount of surface material was recovered and was analyzed by PXRD. The melt extrudates with EPO at all ratios showed the presence of amorphous drug in SGF and SIF (Fig. 9). However, the drug in melt extrudate with PVPVA and PVP K30 was converted to crystalline form at the surface during the dissolution studies (Fig. 10).

The solid solutions with EPO, PVPVA, and PVPK30 showed improved dissolution rate due to conversion to the high-energy amorphous form of the drug. The amorphous INM in solid solutions showed tendency to convert back to crystalline form, which was dependent on dissolution media, nature, and concentration of polymer.

Stability Studies Stability studies were carried out to establish the physical stability of the amorphous drug at the accelerated conditions. All formulations were stored at 408C and 75% relative humidity conditions for 3 months in an open vial. Various analytical techniques were used to monitor the physical stability of the amorphous drug, such as DSC, PXRD, and IDR studies. After 3 months accelerated stability, the melt extrudate of drug with EPO showed no depression in glass transition temperature as compared to the initial samples (Tab. 5). PXRD also conrmed the amorphous nature of INM on stability. The consistent solid-state properties after storage at accelerated conditions suggest that amorphous IND was stable in melt extrudate with EPO. This was further conrmed by IDR studies showing similar dissolution rates for initial and stability samples (Tab. 6 and Fig. 11). The melt extrudates with PVPK30 and PVPVA stored at accelerated conditions displayed a slightly lower glass transition temperature compared to the initial samples (Tab. 5). That can be attributed to the hygroscopic nature of the
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Figure 10. PXRD of melt extrudates with PVPK30 in SGF. [Color gure can be seen in the online version of this article, available on the website, www.interscience. wiley.com.]
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Table 6. IDR Comparing Initial and 3 Months 408C/75% RH Formulations in SGF and SIF
2

Formulations

IDR in mg/cm min Initial

IDR in mg/cm2 min 3 Months 408C/75% RH 1.52 0.12 2.13 0.21 1.63 0.06 0.92 0.01 1.09 0.16 0.42 0.06 1.10 0.11 0.98 0.17 0.02 0.01

Formulation with EPO HME in SGF drug:polymer HME 70:30 1.47 0.04 HME 50:50 2.21 0.13 HME 30:70 1.79 0.21 Formulation with PVPVA HME in SIF drug:polymer HME 70:30 0.94 0.16 HME 50:50 1.13 0.19 HME 30:70 0.65 0.09 Formulation with PVPK30 HME in SIF (drug:polymer) HME 70:30 1.04 0.05 HME 50:50 0.91 0.07 HME 30:70 0.30 0.01
HME, hot-melt extrudate.

polymer. However, PXRD conrmed the amorphous nature of the drug in stability samples. The IDR after 3 months storage at accelerated condition were similar to that of initial formulations with lower concentration of polymer that is drug to polymer ratio of 70:30 and 50:50 (Tab. 6). However, the formulation with higher amount of polymer (30:70) showed slight decrease in IDR in SIF (Tab. 6, Figs. 12 and 13). The observed decrease in IDR for 30:70 ratio was 1.6-fold and 15-folds for PVPVA and PVPK30 system, respectively. This could be attributed to the hygroscopic nature of the polymer. The higher concentration of

polymer will absorb more water and hence less protection is provided to the amorphous drug. To further evaluate this hypothesis, the moisture content of stressed samples was determined by Karl Fischer technique. As shown in Figure 14, the melt extrudates with higher amount of polymer tend to absorb more water, thus mediating the conversion of amorphous drug to crystalline form. Furthermore, PVPK30 system showed biphasic dissolution prole. During the dissolution 1.8-fold decrease in IDR (from 0 to 40 min and 4080 min) was observed for both initial and stability sample (Fig. 13). This observed decrease in dissolution

Figure 11. The dissolution prole comparing initial and 3 months 408C/75% RH melt extrudate with EPO in SGF. [Color gure can be seen in the online version of this article, available on the website, www.interscience. wiley.com.]
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Figure 12. The dissolution prole comparing initial and 3 months 408C/75% RH melt extrudate with PVP VA in SIF. [Color gure can be seen in the online version of this article, available on the website, www. interscience.wiley.com.]
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Figure 13. The dissolution prole comparing initial and 3 months 408C/75% RH melt extrudate with PVPK30 in SIF. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]

rates suggested that the rate-controlling mechanism is consistent for both samples but different from storage-mediated changes. This could be due to differential dissolution rate of drug and polymers resulting in drug-enriched surface layer during dissolution.

SUMMARY AND CONCLUSION

The hot-melt extrusion was proven to be efcient technology to formulate and stabilize the solid solutions of low Tg model drug INM with the selected polymers such as EPO, PVPVA, and PVPK30. The drug formed one phase system that is solid solution with EPO, PVPVA, and PVPK30 and was found to be present in amorphous form at various ratios. The IDR and solubility were signicantly improved in case of solid solution that was attributed to the high-energy amorphous form of the drug. Although, melt extrudates with EPO showed comparatively lower glass transition temperature, these formulations showed superior stability. Higher amounts of EPO in the formulations facilitated stabilization of the amorphous form of the drug. The melt extrudates with PVP VA and PVPK30 showed higher glass transition temperatures, however, these formulations were more susceptible to conversion during dissolution or storage stability. In conclusion, the solid solutions improved the solubility and IDR of the poorly water-soluble model drug. The glass transition temperature was
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Figure 14. The moisture content of the melt extrudates comparing initial and stability samples. [Color gure can be seen in the online version of this article, available on the website, www.interscience.wiley.com.]
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not the only factor determining the stability of the formulations but also nature and concentration of polymer played a vital role in stabilizing the amorphous nature of the drug. Thus, the model drug with low Tg such as INM (428C) can be stabilized by the appropriate selection of polymer and concentration.

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