Supersaturated Drug Solutions Research Articles

Recent Advances in Transdermal Drug Delivery System (TDDS): A Review

Abstract: The transdermal route of administration has many advantages over more traditional routes of drug administration. They contain high bioavailability, lack of first-pass hepatic metabolism, stable plasma drug concns., and fact that the treatment is non-invasive. The biggest barrier to the penetration of medicinal molecules is the outer layer of the skin, stratum corneum. Thus, research to improve transdermal drug delivery (TDD) is worthwhile this layer is the area of interest. This review article is written to provide coverage commentary recent advances in TDD improvement techniques. Techniques that improve the permeability of the skin have been used developed to improve bioavailability and increase the choice of topical and transdermal drugs is a viable option. This review describes enhancement techniques based on drug/vehicle optimization, e.g selection of drugs, prodrugs and ion pairs, supersaturated drug solutions, eutectic systems, complexes, liposomes, vesicles and particles. Strengthening by changing the shell with moisturizing chemical enhancers partitioning and solubility effects affecting crustal lipid and keratin structure discussed Mechanism of action of penetration enhancers and retarders and their potential for clinical use application is described.

Amorphous solid dispersions of triclabendazole: Keeping the supersaturated drug solution using poloxamers

The dissolution performance of amorphous solid dispersions often leads to the formation of supersaturated drug solutions. However, in many cases, the drugs can recrystallize from those solutions and precipitate. Thus, this study evaluates whether two selected poloxamers, as carriers of amorphous solid dispersions, could avoid the recrystallization and further precipitation of the hydrophobic triclabendazole. Different systems were prepared by the melting method and then characterized in solid and liquid states. The findings indicated that the drug solubility increased more than twenty times, from 0.3 μg/mL (raw drug) to 3.53 μg/mL and 7.28 μg/mL in the presence of P188 and P237, respectively. A similar finding was observed for the drug dissolution, and P188 and P237 increased the drug dissolution to 90 and 100 %, respectively. This study also confirmed that P237 was more effective than P188 in avoiding drug precipitation. As seen by X-ray diffraction analysis, an almost complete amorphization of the drug was observed by increasing the ratio of the poloxamers. Thus, these findings help to understand the dissolution behavior and supersaturated state of triclabendazole from amorphous solid dispersions, which could be applied to other hydrophobic drugs.

The inherent AIE feature revealed the drug molecular state in cyclodextrin metal–organic framework for enhanced stability and absorption

The amorphous form of a drug can greatly improve the solubility and rates of dissolution for enhancing oral bioavailability. However, amorphous drugs tend to crystallize thus negating their solubility advantages. Here, we use a nanoconfinement strategy to prevent the crystallization of amorphous solids by loading the poorly soluble drug indomethacin (IMC) into a porous γ-cyclodextrin-based metal–organic framework (CD-MOF). The inherent aggregation-induced emission (AIE) property of IMC was successfully applied as a sensitive fluorescence imaging tool to visualize its molecular state in the solid form. A distinct high-energy, non-aggregated molecular state of IMC in CD-MOF was revealed by the AIE turn-off phenomenon together with other solid-state characterization methods. The IMC@CD-MOF exhibited excellent physical stability even when stored at high temperature or humidity. The high supersaturated drug solutions were immediately generated and maintained during the dissolution of IMC@CD-MOF, resulting in a great enhancement of in vivo bioavailability. The inherent AIE feature of drugs can facilitate the understanding of the structure–property relationship in complex delivery systems, which is essential for the design and optimization of drug carriers with desired stability and biopharmaceutical performance.

Solid amorphous formulations for enhancing solubility and inhibiting Erlotinib crystallization during gastric-to-intestinal transfer

The objective of this study was to improve the solubility and inhibit the crystallisation during the gastric-to-intestinal transfer of Erlotinib (ERL), a small molecule kinase inhibitor (smKI) compound class, which is classified as class II drug in the Biopharmaceutical Classification System (BCS). A screening approach combining different parameters (solubility in aqueous media, inhibitory effect of drug crystallisation from supersaturated drug solutions) was applied to selected polymers for the development of solid amorphous dispersions of ERL. ERL solid amorphous dispersions formulations were then prepared with 3 different polymers (Soluplus®, HPMC-AS-L, HPMC-AS-H) at a fixed drug: polymer ratio (1:4) by two different production methods (spray drying and hot melt extrusion). The spray-dried particles and cryo-milled extrudates were characterized by thermal properties, shape and particle size, solubility and dissolution behavior in aqueous media. The influence of the manufacturing process on these solid characteristics was also identified during this study. Based on the obtained results, it is concluded that the cryo-milled extrudates of HPMC-AS-L displayed better performance (enhanced solubility, reduced ERL crystallization during the simulated gastric-to-intestinal transfer) and represents a promising amorphous solid dispersion formulation for oral administration of ERL.

Characterizing the Impact of Chitosan on the Nucleation and Crystal Growth of Ritonavir from Supersaturated Solutions

The addition of polymeric materials is often used to delay nucleation or crystal growth and maintain the high supersaturation of amorphous drugs. Therefore, this study aimed to investigate the impact of chitosan on the supersaturation behavior of drugs with a low recrystallization tendency and elucidate the mechanism of its crystallization inhibition in an aqueous solution. It was carried out using ritonavir (RTV) as a model of poorly water-soluble drugs categorized as class III of Taylor's classification, while chitosan was used as a polymer, and hypromellose (HPMC) was used for comparison. The inhibition of the nucleation and crystal growth of RTV by chitosan was examined by measuring the induction time. The interactions of RTV with chitosan and HPMC were evaluated by NMR measurements, FT-IR, and an in silico analysis. The results showed that the solubilities of amorphous RTV with and without HPMC were quite similar, while the amorphous solubility was significantly increased by the chitosan addition due to the solubilization effect. In the absence of the polymer, RTV started to precipitate after 30 min, indicating that it is a slow crystallizer. Chitosan and HPMC effectively inhibited the nucleation of RTV, as reflected by a 48-64-fold enhancement in the induction time. Furthermore, NMR, FT-IR, and in silico analysis demonstrated that the hydrogen bond interaction between the amine group of RTV and a proton of chitosan, as well as the carbonyl group of RTV and a proton of HPMC, was observed. This indicated that the hydrogen bond interaction between RTV and chitosan as well as HPMC can contribute to the crystallization inhibition and maintenance of RTV in a supersaturated state. Therefore, the addition of chitosan can delay nucleation, which is crucial for stabilizing supersaturated drug solutions, specifically for a drug with a low crystallization tendency.

Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity

Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.

NMR-Based Mechanistic Study of Crystal Nucleation Inhibition in a Supersaturated Drug Solution by Polyvinylpyrrolidone

NMR-Based Mechanistic Study of Crystal Nucleation Inhibition in a Supersaturated Drug Solution by Polyvinylpyrrolidone

Revealing the roles of polymers in supersaturation stabilization from the perspective of crystallization behaviors: A case of nimodipine

Formulating drugs into amorphous solid dispersions (ASDs) represents an attractive means to enhance the aqueous solubility of drugs. Furthermore, water-soluble polymers have proven highly advantageous for stabilizing supersaturated solutions of ASDs. However, the performance and mechanism of various polymers in stabilizing supersaturated drug solutions have not been well-studied. The aim of this study was to investigate the effects of different commercial polymers on the dissolution behaviors and supersaturation stabilization of the ASDs and to further explore the mechanism of polymer mediated supersaturation maintenance by studying the crystallization behaviors of the ASDs. In this study, nimodipine (NMD) was used as a model drug because of its poor water-solubility and fast crystallization rate in aqueous solution, and three polymers polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (PVP VA), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) was selected as the drug carriers to form the ASDs with NMD. Solid-state characterizations of the ASDs confirmed the amorphous state of the ASD systems. ASDPVP VA demonstrated superior supersaturation maintenance in dissolution experiments compared to the other two ASD systems. Among the polymers tested, PVP VA most efficiently maintained dissolution of NMD and prevented its crystallization from the supersaturated solution. The ability of PVP VA to most-effectively maintain supersaturation of the drug was manifested by inhibition of crystal nucleation rather than inhibition of crystal growth following nucleation. These results suggest that nucleation inhibition was instrumental in enabling the polymer-mediated supersaturation maintenance, at least with NMD.

Laser diffraction as a powerful tool for amorphous solid dispersion screening and dissolution understanding

Biopharmaceutics Classification System (BCS) class II and IV drugs may be formulated as supersaturating drug delivery systems (e.g., amorphous solid dispersions [ASDs]) that can generate a supersaturated drug solution during gastrointestinal (GI) transit. The mechanisms that contribute to increased bioavailability are generally attributed to the increased solubility of the amorphous form, but another mechanism with significant contributions to the improved bioavailability have been recently identified. This mechanism consists on the formation of colloidal species and may further improve the bioavailability several fold beyond that of the amorphous drug alone. These colloidal species occur when the concentration of drug generated in solution exceeds the amorphous solubility during dissolution, resulting in a liquid-liquid phase separation (LLPS). For the appearance of LLPS, the crystallization kinetics needs to be slow relatively to the dissolution process. This work intended to implement an analytical methodology to understand the ability of a drug to form colloidal species in a biorelevant dissolution media. This screening tool was therefore focused on following the colloidal formation and crystallization kinetics of itraconazole (ITZ; model drug from BSC class II) in the presence of hydroxypropyl methylcellulose (HPMC-AS L and HPMC-AS M, which are HPMC-AS with varying ratios of succinoyl:acetyl groups), using a laser diffraction-based methodology. The ability of ITZ to form colloids by a solvent-shift approach was compared with the actual colloidal formation of ITZ amorphous solid dispersions produced by spray-drying. Results indicate that regardless of the used methodology, colloids of ITZ can be detected and monitored. The extension of colloid generation showed to be correlated with the ASD disintegration/dissolution rate, i.e, polymers with faster wettability kinetics led to faster ASD disintegration and colloidal formation.As conclusion, this study showed that laser diffraction could give complementary information about colloidal formation and ASD dissolution profile, showing to be an excellent screening strategy to be applied in the early stage development of amorphous solid dispersions.

Molecular Mobility Suppression of Ibuprofen-Rich Amorphous Nanodroplets by HPMC Revealed by NMR Relaxometry and Its Significance with Respect to Crystallization Inhibition

In the present study, the molecular state of drug-rich amorphous nanodroplets was evaluated using NMR techniques to reveal the mechanism underlying the crystallization inhibition of drug-rich amorphous nanodroplets by a polymer. Ibuprofen (IBP) with a low glass transition temperature was used for direct characterization of drug-rich amorphous nanodroplets. Highly supersaturated IBP formed IBP-rich amorphous nanodroplets through phase separation from aqueous solution. Increasing the concentration of hypromellose (HPMC) in the aqueous solution contributed to the inhibition of IBP crystallization and maintenance of supersaturation at IBP amorphous solubility. Solution 1H NMR measurements of IBP supersaturated solution containing IBP-rich amorphous nanodroplets clearly showed two kinds of 1H peaks derived from the dissolved IBP in bulk water phase and phase-separated IBP in IBP-rich amorphous nanodroplets. NMR spectral analysis indicated that HPMC did not affect the chemical environment and mobility of the dissolved IBP. However, 1H spin-spin relaxation time measurements clarified that the dissolved IBP in the bulk water phase was exchanged with the IBP-rich amorphous nanodroplets with an exchange lifetime of more than 10 ms. Moreover, the 1H peaks of HPMC partially disappeared due to the formation of IBP-rich amorphous nanodroplets, suggesting that a part of HPMC distributed into the IBP-rich amorphous nanodroplets from the bulk water phase. The incorporation of HPMC significantly changed the chemical environment of the phase-separated IBP in the IBP-rich amorphous nanodroplets and strongly suppressed molecular mobility. The resulting molecular mobility suppression effectively inhibited IBP crystallization from the IBP-rich amorphous nanodroplets. Thus, direct investigation of drug-rich amorphous nanodroplets using NMR can be a promising approach for selecting appropriate pharmaceutical excipients to suppress drug crystallization in supersaturated drug solutions.

Exploration of supersaturable lacidipine ternary amorphous solid dispersion for enhanced dissolution and in vivo absorption

Amorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6–7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0–∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.

Synergistic effect of Soluplus and hyaluronic acid on the supersaturation maintenance of lovastatin: The facilitated in vitro-in vivo performance and improved physical stability

The objective of present study was to explore whether polysaccharide could be employed as potential crystal growth inhibitor and provides synergistic effect on the supersaturation maintaining of lovastatin (LOV) in combination of nucleation inhibitor. Soluplus (SOL) and hyaluronic acid (HA) were selected as the most effective nucleation and crystal growth inhibitor respectively. The interaction between SOL and HA was elucidated via characterizing the particle size, zeta potential, surface hydrophobicity, solvent relaxation time (T2) and FT-IR. The supersaturated drug solution was spray dried into amorphous solid dispersion, then, the in vitro release, moisture uptake and physical stability were investigated. The synergistic effect between SOL and HA was dependent on drug concentration, drug/carrier and SOL/HA weight ratio, which facilitated both in vitro and in vivo performance. It was disclosed that HA could insert into SOL structure providing both electrostatic and steric stabilization. In conclusion, the combination of nucleation and crystal growth inhibitors is a promising approach for supersaturated drug delivery system.

Synergetic effect of nucleation and crystal growth inhibitor on in vitro-in vivo performance of supersaturable lacidipine solid dispersion

Limited supersaturation maintaining duration is the main challenge for amorphous solid dispersion design. Nucleation or crystal growth inhibitors may function in different ways but the combination use of nucleation and crystal growth inhibitors in supersaturated system is rarely explored. Thus, using Lacidipine (LCDP) as a Biopharmaceutical Classification System (BCS) II model drug, the aim of this study was to explore whether the combination use of nucleation and crystal growth inhibitors could provide a synergistic effect on the in vitro-in vivo performance of poorly water-soluble drugs. First of all, based on compatibility screening using solubility parameter (Δδ) and crystallization inhibition efficiency as criteria, soluplus (SOL) and gum arabic (GA) were selected as the most effective nucleation and crystal growth inhibitor respectively. Thereafter, the supersaturated drug solutions were spray dried and characterized. The in vitro release, physical stability as well as pharmacokinetic behavior were investigated. It was found that the combination use of SOL and GA did not present remarkable advantage in prolonging the supersaturation time in solution state. However, their synergistic effect in equilibrium solubility and dissolution enhancement was noticed at SOL/GA ratio 3:1, with 5–7 times higher dissolution rate observed for LCDP/SOL/GA based formulation compared with that of LCDP/SOL, which was maintained even after three months accelerated stability test under non-sink condition. Moreover, compared to the LCDP/SOL formulation, approximately 2.8 and 2.5-fold increase in the maximum plasma concentration (Cmax) and the area under the plasma-time curve (AUC0–∞) was achieved with LCDP/SOL/GA based formulation. Possible mechanism of the synergistic effect was elucidated, indicating GA may penetrate into SOL particles providing both electrostatic and steric stabilization. In conclusion, the combination use of screened nucleation and crystal growth inhibitors might be an efficient approach to design supersaturated drug delivery system.

Conjugation of bile esters to cellulose by olefin cross-metathesis: A strategy for accessing complex polysaccharide structures

Bile salts tend to form micelles in aqueous media and can thereby contribute to drug solubilization; they also exhibit crystallization inhibition properties that can stabilize supersaturated drug solutions. Herein, we explore conjugation of bile salts with polysaccharides to create new, amphiphilic polysaccharide derivatives with intriguing properties, portending broad utility in various applications. We introduce efficient conjugation of cholesterol (as a model steroid), lithocholic acid, and deoxycholic acid by mild, modular olefin cross-metathesis reactions. These small molecules were first modified with an acrylate group from the A-ring hydroxyl, then reacted with cellulose derivatives bearing olefin-terminated metathesis “handles”. Successful conjugation of bile acids has demonstrated chemoselective cross-metathesis with complex, polyfunctional structures, and large multi-ring systems. It also enabled an efficient, general pathway for polysaccharide-bile salt conjugates, which promise synergy for applications such as amorphous solid dispersion (ASD).

Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions

In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).

Crystallization Inhibition Properties of Cellulose Esters and Ethers for a Group of Chemically Diverse Drugs: Experimental and Computational Insight.

Amorphous solid dispersions are widely used to enhance the oral bioavailability of poorly water-soluble drugs. Polymeric additives are commonly used to delay crystallization of the drug from the supersaturated solutions formed upon ASD dissolution by influencing the nucleation and growth of crystals. However, there is limited evidence regarding the mechanisms by which polymers stabilize supersaturated drug solutions. The current study used experiments and computational modeling to explore polymer-drug interactions in aqueous solutions. Nucleation induction times for supersaturated solutions of nine drugs in the presence of five newly synthesized cellulose-based polymers were evaluated. The polymers had carboxylic acids substituents with additional variations in the side-chain structure: (1) one with a single side chain and a carboxylic acid termination, (2) three with a branched side chain terminated with a carboxylic and an alcohol group (varying the cellulose linkage and the length of the hydrocarbon side chain), and (3) one with a branched side chain with two carboxylic acid end groups. The polymers with a short side chain and one carboxylic acid were effective, whereas the polymers with the two carboxylic acids or a long hydrocarbon chain were less effective. Atomic force microscopy experiments, evaluating polymer adsorption onto amorphous drug films, indicated that the effective polymers were uniformly spread across the surface. These results were supported by molecular dynamics simulations of a polymer chain in the presence of a drug aggregate in an aqueous environment, whereby the effective materials had a higher probability of establishing close contacts and more negative estimated free energies of interaction. The insights provided by this study provide approaches to design highly effective polymers to improve oral drug delivery.

Mechanistic understanding of the phase behavior of supersaturated solutions of poorly water-soluble drugs

Amorphous solid dispersions (ASDs) are a promising formulation strategy to increase both the apparent aqueous solubility and bioavailability of poorly water-soluble drugs. Upon dissolution under nonsink conditions, ASDs can generate highly supersaturated drug solutions which can undergo liquid–liquid phase separation (LLPS) and/or crystallization. In this study, the phase behavior of supersaturated solutions generated by antisolvent addition and upon the dissolution of ASDs was evaluated using fluorescence lifetime measurements and several other orthogonal techniques, including steady-state fluorescence spectroscopy, ultraviolet (UV) extinction and concentration profiles, ultracentrifuge measurements and nanoparticle tracking analysis. Ritonavir and lopinavir were chosen as poorly water-soluble model drugs, and the polymer, Kollidon VA64, was selected to form the dispersions. The fluorescence lifetime of the environment-sensitive fluoroprobe, PRODAN, was monitored to determine the occurrence of LLPS and crystallization. It was found that only the 10% w/w drug loading ASDs dissolved to a concentration in solution higher than the LLPS concentration and this led to an increase in the lifetime of PRODAN due to partitioning of the fluoroprobe into the drug-rich phase. In contrast, the 50% w/w drug loading ASDs did not reach the amorphous solubility, pointing to a dissolution behavior controlled by the low water solubility and high hydrophobicity of the drug. Fluorescence lifetime measurements were demonstrated to be extremely useful for the characterization of the phase behavior of supersaturated solutions of poorly water-soluble drugs.

Tri-block polymer with interfacial layer formation ability and its use in maintaining supersaturated drug solution after dissolution of solid dispersions

BackgroundMaintaining a supersaturated drug solution after the dissolution of the solid dispersions of water insoluble drugs continues to be a great challenge and is important to the oral bioavailability enhancement of hardly soluble drugs.MethodsNimodipine solid dispersions were prepared by hot-melt extrusion and a special tri-block polymer was employed as a co-carrier. The solid dispersions were characterized by modulated differential scanning calorimetry, transmission electron microscopy, hydrogen-nuclear magnetic resonance and so on.ResultsThe tri-block polymer was able to inhibit the formation of drug crystals after dissolution of the solid dispersions. Due to the unique interfacial layer formation ability of the tri-block polymer, a special drug loading micelle which encapsulated the compound and the hydrophobic fragments of the copolymers appeared in the release media. The tri-block polymer was composed of a hydrophilic part forming the shell of micelles, a hydrophobic part shaping the core of micelles, and a special intermediate hydrophilicity part constructing the interfacial layer of micelles.ConclusionThe tri-block polymer was not only able to stabilize the supersaturated drug solution of solid dispersions to enhance the oral bioavailability of hardly soluble drugs, but is also a potential candidate to construct micelles for systemic administration, due to the good compatibility and organic solvents free micelle formation procedure.

Paclitaxel Crystal Seeds with Different Intrinsic Properties and Their Impact on Dissolution of Paclitaxel-HPMCAS Amorphous Solid Dispersions

Dissolving a formulation containing the drug in amorphous form can lead to supersaturation and increase the free drug concentration relative to that achieved by dissolving the crystalline form. However, the amorphous form is thermodynamically metastable, and hence crystallization can occur both in the formulation and from the supersaturated drug solution generated upon dissolution. From a practical perspective, it may not be possible to always produce amorphous solid dispersions (ASDs) that are completely free of residual crystallinity. Crystals formed in different environments can have dissimilar intrinsic properties, which in turn can influence crystal growth kinetics and hence the dissolution profile of the ASD. Herein, paclitaxel, a compound that crystallizes as needles, was used as a model compound to explore the impact of crystal seeds on the (de)supersaturation profile obtained following dissolution of an amorphous solid dispersion. Crystal seeds generated under four different conditions had differ...

Screen for Inhibitors of Crystal Growth to Identify Desirable Carriers for Amorphous Solid Dispersions Containing Felodipine.

The solvent-shift method was used to identify appropriate polymers that inhibit the growth of felodipine crystals by monitoring particle size in supersaturated drug solutions in the presence of different polymers. We speculated that there would be an intermolecular interaction between the selected polymer (zein) and felodipine by extrapolating the inhibitory effect on crystal growth and then used the selected polymer as a carrier to prepare solid dispersions. The formulations were characterized by crystalline properties, thermodynamics of mixing, dissolution behavior, and physical stability. Powder x-ray diffraction and differential scanning calorimetry experiments indicated that amorphous solid dispersions were formed when the proportion of felodipine was < 30% (w/w). Stability tests showed that a solid dispersion with 20% felodipine remained in an amorphous state and was stable under accelerated storage conditions for 6months. The dissolution rates of solid dispersions were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Analysis by Fourier-transform infrared spectroscopy and Raman microspectroscopy indicated the formation of intermolecular interactions between zein and felodipine. The study demonstrates the successful application of the chosen polymer as a carrier in solid dispersions and validates the concept of extrapolating the inhibitory effect on crystal growth to intermolecular interactions.