Evaluation of Drug Supersaturation by Thermodynamic and Kinetic Approaches for the Prediction of Oral Absorbability in Amorphous Pharmaceuticals

Supersaturation behavior of model drugs, danazol, griseofulvin, itraconazole, vemurafenib, and ER-34122, was analyzed by both thermodynamic and kinetic approaches to better understand the absorption characteristics of amorphous pharmaceuticals. For each amorphous drug, the extent of supersaturation during in vitro dissolution was proved to be similar to that in vivo, which was estimated from relative bioavailability data. The theoretical limit of supersaturation was thermodynamically calculated from several thermal properties and water sorption isotherms of amorphous solids. in vitro and in vivo supersaturation of amorphous vemurafenib was thermodynamically controlled and was in good agreement with the theoretical limit. On the contrary, the supersaturation ratio of the other four drugs was highly overestimated by the thermodynamic calculation. However, it was satisfactorily explained by considering supersaturation stability, which indicated how long supersaturation can be maintained without crystal nucleation. Supersaturation stability was evaluated by measuring the induction time for crystal nucleation kinetically. Concomitant use of thermodynamic and kinetic approaches is, therefore, invaluable in evaluating supersaturation behavior of amorphous materials and assessing development potential of poorly water-soluble drugs. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4220–4230, 2012     

Correlation of Inhibitory Effects of Polymers on Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction

Purpose

To correlate the polymer’s degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state.

Methods

Precipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers.

Results

PVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90?>?Eudragit E100?>?HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers.

Conclusions

Correlation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.     

Correlating the Behavior of Polymers in Solution as Precipitation Inhibitor to its Amorphous Stabilization Ability in Solid Dispersions

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization.     

Effect of biocompatible polymers on the physicochemical and dissolution properties of fenofibrate in nanoparticle system

This study aimed to evaluate the effect of biocompatible polymers on the physicochemical and dissolution properties of poorly water-soluble drugs in nanoparticle systems. Four types of nanoparticles containing poorly water-soluble fenofibrate were prepared using solvent evaporation technique with different biocompatible polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), carbopol and ethylcellulose. Their physicochemical properties were investigated using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. The solubility and dissolution of nanoparticle-entrapped fenofibrate were compared with those of free drug powder. Biocompatible polymers affected the morphology and sizes of fenofibrate nanoparticles. PVP or carbopol-based nanoparticles showed spherical appearance, whereas HPMC or ethylcellulose-based nanoparticles formed aggregates with irregular shape. The particle sizes increased in the order of the nanoparticle prepared with carbopol ≤ PVP < HPMC < ethylcellulose. The size of PVP-based nanoparticles did not significantly differ from that of carbopol-based nanoparticles, showing the mean sizes of ca. 10 μm. As compared to free drug powder, the solubility and dissolution of the drug in nanoparticles increased in the order of PVP > HPMC > carbopol > ethylcellulose. The enhanced solubility and dissolution of poorly water-soluble fenofibrate via nanoparticle system did not depend on particle size but on crystallinity. In conclusion, in nanoparticle development of poorly water-soluble drugs such as fenofibrate, the nature of biocompatible polymers plays an important role in the physicochemical and dissolution of poorly water-soluble drugs in the nanoparticles.     

Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine

Amorphous solid dispersions are used as a strategy to improve the bioavailability of poorly water-soluble compounds. When formulating with a polymer, it is important not only for the polymer to stabilize against crystallization in the solid state, but also to improve the dissolution profile through inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. In this study, the dissolution profiles of solid dispersions of felodipine formulated with poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) were compared. In addition, concentration versus time profiles were evaluated for the supersaturated solutions of felodipine in the presence and absence of the polymers. HPMCAS was found to maintain the highest level of supersaturation for the greatest length of time for both the dissolution and solution crystallization experiments, whereas PVP was found to be the least effective crystallization inhibitor. All polymers appeared to reduce the crystal growth rates of felodipine at an equivalent supersaturation and this mechanism most likely contributes to the enhanced solution concentration values observed during dissolution of the amorphous solid dispersions.     

Polymer incorporation method affects the physical stability of amorphous indomethacin in aqueous suspension

This study reports the potential of different polymers and polymer incorporation methods to inhibit crystallisation and maintain supersaturation of amorphous indomethacin (IND) in aqueous suspensions during storage. Three different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) and Soluplus® (SP)) were used and included in the suspensions either as a solid dispersion (SD) with IND or dissolved in the suspension medium prior to the addition of amorphous IND. The total concentrations of both IND and the polymer in the suspensions were kept the same for both methods of polymer incorporation. All the polymers (with both incorporation methods) inhibited crystallisation of the amorphous IND. The SDs were better than the predissolved polymer solutions at inhibiting crystallisation. The SDs were also better at maintaining drug supersaturation. SP showed a higher IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. IND in SD with SP did not crystallise, nor did the SD generate any drug supersaturation, whereas IND in the corresponding predissolved SP solution crystallised (into the recently characterised η polymorphic form of the drug) but also led to a more than 20-fold higher IND solution concentration than that observed for crystalline IND. The ranking of the polymers with respect to crystallisation inhibition potential in SDs was SP ≫ PVP > HPMC. Overall, this study showed that both polymer type and polymer incorporation method strongly impact amorphous form stability and drug supersaturation in aqueous suspensions.     

Crystallization of hydrocortisone acetate: influence of polymers

The influence of hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG400) on the crystallization of hydrocortisone acetate (HA) was studied. Supersaturation was created by the cosolvent technique. Spontaneous nucleation was observed when no polymer was used as the additive. In the presence of the polymer, nucleation was delayed. The nucleation time decreased with increasing supersaturation at a particular polymer concentration and increased with increasing polymer concentration at a particular supersaturation. Habit modification from a well-defined polar prismatic morphology to a wing-shaped morphology was observed when HPMC was used as the additive. The effect of PVP and PEG400 on the morphology of HA was less pronounced compared to the cellulose polymers. The mechanism of nucleation retardation by the polymers is explained in terms of association of HA with the polymer through hydrogen bonding. The growth may be inhibited by the hydrodynamic boundary layer, in which the polymers accumulate as well as by the adsorption of the polymer onto the crystal surface. The habit modification of HA by HPMC is due to different extents of adsorption on different faces of the crystal, the extent of which is dependent on the hydrogen bonding functional groups that are exposed at each face of the crystal.     

Coaxial electrospray formulations for improving oral absorption of a poorly water-soluble drug

Development of oral dosage forms containing poorly water-soluble drugs is a major challenge in the pharmaceutical industry. This paper describes the use of coaxial electrospray deposition as a promising formulation technology for oral delivery of poorly water-soluble drugs. The technology produced core-shell particles composed of griseofulvin and poly(methacrylic acid-co-methyl methacrylate) (Eudragit L-100), with a diameter of around 1 μm. The drug phase was in an amorphous state when the griseofulvin core was coated with the Eudragit L-100 shell. The in vitro dissolution and in vivo oral absorption studies revealed that the core-shell formulation significantly improved dissolution and absorption behaviors, presumably because of a reduction in particle size, improvement in dispersity, and amorphization. Results demonstrated that coaxial electrospray deposition possesses great potential as novel formulation technology for enhancing oral absorption of poorly water-soluble drugs.     

Formulation optimization of solid dispersion of mosapride hydrochloride

Mosapride citrate (MSP) is a gastroprokinetic agent that acts as a selective 5-HT₄ agonist and accelerates the gastric emptying, and is used for the treatment of acid reflux, irritable bowel syndrome, and functional dyspepsia. The purpose of this study is to investigate the solid dispersion formulations of MSP with controlled release characteristic using various polymers, elucidate the release mechanism, and characterize the interaction patterns between MSP and polymers. Solid dispersions of MSP with different drug-to-polymer ratios were prepared by a solvent evaporation method and characterized in comparison with the simple physical mixtures. Eudragit RSPO, Eudragit RLPO, hydroxypropylmethylcellulose (HPMC) or Kollidon SR® was used as a controlled-release polymer along with polyvinylpyrrolidone (PVP) as a carrier. Characterization of MSP solid dispersion was performed using thermal analysis (DSC), powder X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, where the drug was converted from the crystalline state to amorphous state in all polymeric carriers used. In vitro dissolution studies showed that the drug release has been extended up to 24 h by using Eudragit RSPO or HPMC. Moreover, the formulations containing higher polymer content ratio showed better slow-release profile. These results indicate that the solid dispersion formulation containing PVP/Eudragit RSPO or HPMC mixture could serve as a good controlled-release system for MSP.     

Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations

Purpose

The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.

Methods

The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.

Results

Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.

Conclusions

Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.

     

Dissolution improvement of four poorly water soluble drugs by cogrinding with commonly used excipients.

The rate of the dissolution of four poorly soluble drugs (EMD 57033, albendazole, danazol and felodipine) was improved by cogrinding them with various excipients (lactose monohydrate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and sodium lauryl sulphate) using a jet-milling technique. Solid state characterization studies by X-ray diffraction and differential scanning calorimetry verified the maintenance of the crystalline state of the active substances after milling. In vitro dissolution of the coground mixtures in biorelevant media was much faster than from micronised drug in the corresponding physical mixtures for all four compounds. Supersaturated solutions were generated in some cases (EMD 50733 and felodipine), but this phenomenon appeared to be drug- and excipient-specific. Cogrinding with lactose monohydrate resulted in fast dissolution with unstable supersaturation for EMD 57033. Cogrinding the same drug with PVP or HPMC produced a more sustained supersaturation. SLS accelerated the dissolution of EMD 50733 but inhibited supersaturation. The results suggest that the cogrinding with selected excipients is a powerful tool to accelerate the dissolution of poorly soluble drugs without converting the drug to the amorphous form or changing the particle size.     

Characterization and stability of solid dispersions based on PEG/polymer blends

Solid dispersions were prepared by a melting method from the water-insoluble model drugs carbamazepine and nifedipine and polyethylene glycol 1500 (PEG 1500) or 1:1 mixtures of PEG 1500 and the polymers polyvinylpyrrolidone (PVP 30, PVP 12), polyvinylpyrrolidone-co-vinylacetate (PVPVA) and Eudragit EPO (Eudragit) in order to combine advantages of the different carrier polymers (recrystallization inhibition, processability and stability). The solid dispersions were characterized by dissolution, powder X-ray diffractometry and microscopy directly after preparation and after storage for 3 and 6 months at 25 °C/0% relative humidity (RH) or 3 months at 40 °C/75% RH. More than 80% drugs were released from all solid dispersions within 20 min. The dissolution rate of carbamazepine decreased in the order of PEG 1500 > PEG 1500/Eudragit > PEG 1500/PVP 30 > PEG 1500/PVPVA > PEG 1500/PVP 12. The dissolution rank order was not directly correlated to the amorphous/crystalline state of the drugs, but rather to the properties of the PEG 1500/polymer compositions. Nifedipine was released in the order of PEG 1500 > PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit. Amorphous nifedipine was present in all PEG 1500/polymer dispersions except in pure PEG 1500 solid dispersion. The significant increase in dissolution rate of PEG 1500 solid dispersions was due to the reduced crystallinity of the drug and the excellent solubilisation properties of PEG 1500. After 6 months storage at 25 °C/0% RH, the solid dispersions released both drugs in the order PEG 1500/PVPVA > PEG 1500/PVP 30 > PEG 1500/PVP 12 > PEG 1500/Eudragit > PEG 1500. The stabilized amorphous state of the drug resulted in stable dissolution profiles of PEG 1500/PVPVA, PEG 1500/PVP 30 and PEG 1500/PVP 12 when compared to the PEG 1500 solid dispersions, which contained a higher amount of crystalline drug. The solid dispersions with PEG 1500/PVPVA or PEG 1500/PVP stored for 3 months at 40 °C/75% RH showed phase separation due to the hygroscopic properties of the polymers. The influence of 10% (w/w) of the solubilisers polyoxyl 40 hydrogenated castor oil (Cremophor), macrogol-15-hydroxystearate (Solutol) and fatty alcohol alkoxylate (Pluronic) on the dissolution rate and the physical state of the drug was significant.     

Accelerated fenofibrate release from spray-dried microparticles based on polymer blends

Fenofibrate-loaded microparticles based on PVP/Eudragit E or HPMC/Eudragit E blends were prepared by spray-drying. The composition of the systems (in particular the polymer/polymer blend ratio and the drug loading) was varied and the resulting key properties were determined (including drug release measurements in 0.1 M HCl, X-ray diffraction studies, solubility measurements and particle size analysis). For reasons of comparison, also the respective physical drug/polymer/polymer mixtures, microparticles based on binary drug/PVP and drug/HPMC blends, the fenofibrate powder as received and a commercially available drug product were investigated. Importantly, highly supersaturated fenofibrate solutions were created upon exposure of the different types of microparticles to the release medium, in contrast to any reference formulation. Also, the presence of co-dissolved Eudragit E led to a significant increase in fenofibrate solubility. At 10 % drug loading, all microparticles were amorphous and drug release stable during one month open storage. However, at 30 % loading, HPMC containing microparticles showed storage instability, due to drug re-crystallization.     

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with β-cyclodextrin and its derivatives (HP-β-CyD and SBE-β-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride–HP-β-CyD–5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 °C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.     

Preparation and characterization of dipyridamole solid dispersions for stabilization of supersaturation: effect of precipitation inhibitors type and molecular weight

Dipyridamole (DPL) is a weakly basic BCS class II drug which precipitates upon entering into intestine leading to pH dependant and variable absorption. Thus, research envisaged focuses on developing formulations that maintain supersaturation following upon acid to neutral pH transition. In an endeavor to accomplish the objective, solid dispersion (SD) with hydroxypropylmethyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) was prepared by a quench cooling method. The three molecular weight grades of HPMC (HPMC E5, HPMC E15 and HPMC E50) and two molecular weight grades of PVP (PVP K30 and PVP K90) were investigated to observe effect of increasing molecular weight on stabilizing DPL supersaturated solutions. Equilibrium solubility studies revealed increase in solubility with both HPMC and PVP with greater benefit from HPMC. In vitro supersaturated dissolution results demonstrated that HPMC formulations provided greater degree and extent of supersaturation as compared to PVP formulations. The formulation with HPMC E50 provided maximum stabilization to supersaturation upon acid to neutral pH transition. Moreover, the effect of increase in molecular weight was more pronounced in HPMC rather than PVP. Stronger interactions were observed for DPL with HPMC, while no interaction was observed with PVP which was evident from Fourier transform infra-red studies. Differential scanning calorimetry and powder X-ray diffraction studies revealed the amorphous state of DPL in SD.     

Stable carbamazepine colloidal systems using the cosolvent technique

The aim of this paper was to prepare stable carbamazepine nanosuspensions containing 10 mg/ml drug concentration by screening different polymers. Stable formulations were created by the cosolvent technique with polyethylene glycol (PEG-300) and water as the cosolvents. Rapid growth of long needle shaped CBZ crystals was observed in the absence of polymer. The presence of hydroxypropyl methylcellulose (HPMC) or methylcellulose (MC) inhibited crystal growth and the mean particle sizes were in the range 10–20 nm. Simultaneous presence of HPMC and polyvinylpyrrolidon (PVP PF17) polymers in CBZ suspensions enhanced the overall stability of the formulations. The additional stability improvement was attributed to the interaction between the polymers by the formation of hydrogen bonds. Suspension stability was evaluated over 5 months where the particle size remained constant. FT-Raman studies showed the existence of form I within the stable CBZ suspensions.     

Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption

Supersaturatable self-emulsifying drug delivery systems (S-SEDDS) were explored to improve the oral absorption of AMG 517, a poorly water-soluble drug candidate. In vitro characterizations indicate the level of Tween 80 in the formulation dictates the initial degree of supersaturation of AMG 517, and, therefore, its precipitation kinetics. The presence of a small amount of cellulosic polymer (e.g., HPMC) effectively sustained a metastable supersaturated state by retarding precipitation kinetics. Precipitates from the S-SEDDS formulations (with HPMC) from in vitro test media were identified as amorphous AMG 517 while crystalline AMG 517 precipitates were found when either HPMC was absent or PVP was present in the formulation. In vivo pharmacokinetic study in Cynomolgus monkeys reveals that the S-SEDDS formulation showed approximately 30% higher mean C(max) and comparable exposure (AUC) of AMG 517 as compared to an aqueous suspension at a dose of 12.5 mg. The rapid absorption characteristics of AMG 517 from the S-SEDDS formulation as evidenced by high C(max) and short T(max) are attributed to a high free drug concentration in vivo, implying a supersaturated state. This case demonstrates that S-SEDDS technology is an effective approach for improving the rate and extent of absorption of poorly soluble drugs.     

Supersaturation,nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: Polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs

The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603 > Eudragit® L-100-55 > AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.     

Maintenance of supersaturation I: indomethacin crystal growth kinetic modeling using an online second-derivative ultraviolet spectroscopic method

Formulations that produce supersaturated solutions after their oral administration have received increased attention as a means to improve bioavailability of poorly water-soluble drugs. Although it is widely recognized that excipients can prolong supersaturation, the mechanisms by which these beneficial effects are realized are generally unknown. Difficulties in separately measuring the kinetics of nucleation and crystal growth have limited progress in understanding the mechanisms by which excipients contribute to the supersaturation maintenance. This paper describes the crystal growth kinetic modeling of indomethacin, a poorly water-soluble drug, from supersaturated aqueous suspensions using a newly developed, online second-derivative ultraviolet spectroscopic method. The apparent indomethacin equilibrium solubility after crystal growth at a high degree of supersaturation (S=6) was approximately 55% higher than the indomethacin equilibrium solubility determined prior to growth, which was attributed to the deposition of a higher energy indomethacin form on the seed crystals. The indomethacin crystal growth kinetics (S=6) was of first order. By comparing the mass transfer coefficients from indomethacin dissolution and crystal growth, it was shown that the indomethacin crystal growth kinetics at S=6 was bulk diffusion controlled. The change in indomethacin seed crystal size distribution before and after crystal growth was determined and modeled using a mass-balance relationship.     

Ability of Different Polymers to Inhibit the Crystallization of Amorphous Felodipine in the Presence of Moisture

Purpose To investigate the ability of various polymers to inhibit the crystallization of amorphous felodipine from amorphous molecular dispersions in the presence of absorbed moisture. Methods Spin coated films of felodipine with poly(vinylpyrrolidone) (PVP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylmethylcellulose (HPMC) were exposed to different storage relative humidities and nucleation rates were measured using polarized light microscopy. Solid dispersions were further characterized using differential scanning calorimetry, infrared spectroscopy and gravimetric measurement of water vapor sorption. Results It was found that the polymer additive reduced nucleation rates whereas absorbed water enhanced the nucleation rate as anticipated. When both polymer and water were present, nucleation rates were reduced relative to those of the pure amorphous drug stored at the same relative humidity, despite the fact that the polymer containing systems absorbed more water. Differences between the stabilizing abilities of the various polymers were observed and these were explained by the variations in the moisture contents of the solid dispersions caused by the different hygroscopicities of the component polymers. No correlations could be drawn between nucleation rates and the glass transition temperature (T _g) of the system. PVP containing solid dispersions appeared to undergo molecular level changes on exposure to moisture which may be indicative of phase separation. Conclusions In conclusion, it was found that for a given storage relative humidity, although the addition of a polymer increases the moisture content of the system relative to that of the pure amorphous drug, the crystallization tendency was still reduced.