Effect of Structurally Related Compounds on Desupersaturation Kinetics of Indomethacin.

PURPOSE: The pharmaceutical literature contains examples wherein desupersaturation from high concentrations does not proceed to equilibrium concentration of the thermodynamically most stable form but remains above equilibrium. The purpose of the current research was to investigate the effect of structurally related compounds on desupersaturation kinetics as a possible explanation for a higher than equilibrium solubility after crystal growth of γ-indomethacin (γ-IMC). METHODS: Three structurally related compounds (SRC) - cis-sulindac (c-SUL), trans-sulindac (t-SUL) and indomethacin-related compound-A (IMC-A) -were investigated. Desupersaturation kinetics to the most stable γ-IMC, in the presence of c-SUL, t-SUL or IMC-A, was measured at pH 2.0. RESULTS: The SRCs c-SUL and t-SUL were effective crystallization inhibitors of IMC, while IMC-A was not a potent crystallization inhibitor of IMC. Among the sulindac isomers, t-SUL was a stronger crystallization inhibitor. The apparent solubility of γ-IMC crystals grown from supersaturated solutions in the presence of SRCs matched the equilibrium solubility of γ-IMC. During crystallization of IMC in the presence of IMC-A, the concentration of IMC-A declined initially but rebounded as supersaturation and crystallization rate of IMC declined, suggesting that IMC-A itself became incorporated in the IMC crystal lattice at higher degrees of IMC supersaturation. CONCLUSIONS: The results suggest that high apparent solubility after crystallization of IMC reported by several authors is not related to the presence of IMC-A impurity. The greater IMC crystal growth rate inhibition by t-SUL than by c-SUL was consistent with the proposed orientation of SUL molecules adsorbed on the IMC crystal, providing a mechanistic understanding of the inhibition.

Development of convenient crystallization inhibition assays for structure-activity relationship studies in the discovery of crystallization inhibitors.

Kidney stone diseases are increasing globally in prevalence and recurrence rates, indicating an urgent medical need for developing new therapies that can prevent stone formation. One approach we have been working on is to develop small molecule inhibitors that can interfere with the crystallization process of the chemical substances that form the stones. For these drug discovery efforts, it is critical to have available easily accessible assay methods to evaluate the potential inhibitors and rank them for structure-activity relationship studies. Herein, we report a convenient, medium-to-high throughput assay platform using, as an example, the screening and evaluation of inhibitors of L-cystine crystallization for the prevention of kidney stones in cystinuria. The assay involves preparing a supersaturated solution, followed by incubating small volumes (<1 mL) of the supersaturated solution with test inhibitors for 72 hours, and finally measuring L-cystine concentrations in the supernatants after centrifugation using either a colorimetric or fluorometric method. Compared to traditional techniques for studying crystallization inhibitors, this miniaturized multi-well assay format is simple to implement, cost-effective, and widely applicable in determining and distinguishing the activities of compounds that inhibit crystallization. This assay has been successfully employed to discover L-cystine diamides as highly potent inhibitors of L-cystine crystallization such as LH708 with an EC50 of 0.058 µM, 70-fold more potent than L-CDME (EC50 = 4.31 µM).

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.

Small molecules interfacial assembly regulate the crystallization transition process for nobiletin stabilization.

Many bioactive nutraceuticals naturally occurring in food materials possess beneficial biological activities, while their use as functional supplements is subjected to hydrophobicity and crystallinity. Currently, inhibiting crystallization for such nutrients is of immense scientific interest. Here, we exploited diverse structural polyphenols as potential inhibitors for restraining Nobiletin crystallization. Specifically, the crystallization transition process could be influenced by the polyphenol gallol density, Nobiletin supersaturation (1, 1.5, 2, 2.5 mM), temperature (4, 10, 15, 25 and 37 ℃), and pH (3.5, 4, 4.5, 5), important factors for regulating the binding attachment and interactions. The optimized samples could be guided by NT100 lied in 4 ℃ at pH 4. Besides, the main assembly driving force was hydrogen-bonding cooperated with π-π stacking and electrostatic interaction, leading to a Nobiletin/TA combination ratio of âˆ¼ 3:1. Our findings proposed an innovative synergistic strategy for inhibiting crystallization and broaden potential applications of polyphenol-based materials in advanced biological fields.

Tree-Inspired Aerogel with a Radial and Centrosymmetric Structure for Efficient Solar-Powered Water Purification.

Solar-powered water purification is one of the promising choices for clean water production. However, it remains challenging to develop aerogel solar evaporators that simultaneously possess enhanced light-to-heat conversion, optimal thermal management, and salt crystal deposition inhibition. Herein, to address this challenge, we have developed a 3D chitosan-reduced graphene oxide/polypyrrole (CS-RGO/PPy) aerogel vaporizer with a vertical and radially aligned structure through a directional freezing process, inspired by the featured structure of conifers. The radially porous walls and vertically arranged channels within the 3D aerogel were able to facilitate high light absorption, localizing converted heat, rapid water transport, and self-salt discharge. Under 1 sun irradiation, the aerogel vaporizer displayed an improved light absorption characteristic of 95% and a high-rate evaporation (∼3.19 kg m-2 h-1) that achieved continuous freshwater from the saturated brine production without solid salt crystallization. Besides achieving seawater desalination, the obtained aerogel could purify organic wastewater and emulsions through solar distillation with high-rate continuous water production.

Supersaturation maintenance of carvedilol and chlorthalidone by cyclodextrin derivatives: Pronounced crystallization inhibition ability of methylated cyclodextrin.

Cyclodextrin (CD) is used to solubilize poorly water-soluble drugs by inclusion complex formation. In this study, we investigated the effect of CD derivatives on stabilizing the supersaturation by inhibiting the crystallization of two poorly water-soluble drugs, carvedilol (CVD) and chlorthalidone (CLT). The phase solubility test showed that ß-CD and γ-CD derivatives enhanced the solubility of CVD to a greater extent, whereas the solubility of CLT was enhanced more by ß-CD derivatives. The solubilization efficacy of CD derivatives was dependent on the size fitness between the drug molecule and the CD cavity. In the drug crystallization induction time measurement, the same initial drug supersaturation ratio (S) was employed in all the CD solutions, and the methylated CD derivatives greatly outperformed unmethylated CD derivatives in stabilizing the supersaturation of both CVD and CLT. The crystallization inhibition strength of CD derivatives was strongly affected by the CD derivative substituent. Moreover, the calculated logarithm of octanol/water partition coefficients (log P) of CD derivatives showed a good correlation with drug crystallization inhibition ability. Thus, the high hydrophobicity of methylated CD plays an essential role in inhibiting crystallization. These findings can provide a valuable guide for selecting appropriate stabilizing agents for drug-supersaturation formulations.

Structural Modifications of Polyethylenimine to Control Drug Loading and Release Characteristics of Amorphous Solid Dispersions.

Crystalline drugs with low solubility have the potential to benefit from delivery in the amorphous form. The polymers used in amorphous solid dispersions (ASDs) influence their maximum drug loading, solubility, dissolution rate, and physical stability. Herein, the influence of hydrophobicity of crosslinked polyethylenimine (PEI) is investigated for the delivery of the BCS class II nonsteroidal anti-inflammatory drug flufenamic acid (ffa). Several synthetic variables for crosslinking PEI with terephthaloyl chloride were manipulated: solvent, crosslinking density, reactant concentration, solution viscosity, reaction temperature, and molecular weight of the hyperbranched polymer. Benzoyl chloride was employed to cap amine groups to increase the hydrophobicity of the crosslinked materials. Amorphous deprotonated ffa was present in all ASDs; however, the increased hydrophobicity and reduced basicity from benzoyl functionalization led to a combination of amorphous deprotonated ffa and amorphous neutral ffa in the materials at high drug loadings (50 and 60 wt %). All ASDs demonstrated enhanced drug delivery in acidic media compared to crystalline ffa. Physical stability testing showed no evidence of crystallization after 29 weeks under various relative humidity conditions. These findings motivate the broadening of polymer classes employed in ASD formation to include polymers with very high functional group concentrations to enable loadings not readily achieved with existing polymers.

Supersaturation and phase behavior during dissolution of amorphous solid dispersions.

Amorphous solid dispersion (ASD) is a promising strategy to enhance solubility and bioavailability of poorly water-soluble drugs. Due to higher free energy of ASD, supersaturated drug solution could be generated during dissolution. When amorphous solubility of a drug is exceeded, drug-rich nanodroplets could form and act as a reservoir to maintain the maximum free drug concentration in solution, facilitating the absorption of the drug in vivo. Dissolution behavior of ASD has received increasing interests. This review will focus on the recent advances in ASD dissolution, including the generation and maintenance of supersaturated drug solution in absence or presence of liquid-liquid phase separation. Mechanism of drug release from ASD including polymer-controlled dissolution and drug-controlled dissolution will be introduced. Formation of amorphous drug-rich nanodroplets during dissolution and the underlying mechanism will be discussed. Phase separation morphology of hydrated ASD plays a critical role in dissolution behavior of ASD, which will be highlighted. Supersaturated drug solution shows poor physical stability and tends to crystallize. The effect of polymer and surfactant on supersaturated drug solution will be demonstrated and some unexpected results will be shown. Physicochemical properties of drug and polymer could impact ASD dissolution and some of them even show opposite effect on dissolution and physical stability of ASD in solid state, respectively. This review will contribute to a better understanding of ASD dissolution and facilitate a rational design of ASD formulation.

Gelation Elimination and Crystallization Inhibition by Co-Amorphous Strategy for Amorphous Curcumin.

In the previous study, the development of amorphous curcumin (CUR) aimed to enhance the solubility/dissolution of CUR by disrupting its crystal lattice, but it unexpectedly showed a decreased dissolution than its crystalline counterpart on account of gel formation in its dissolution process. Whether such gelation could be eliminated by co-amorphous strategy was answered in this study. Herein, CUR by co-amorphization with chlorogenic acid (CHA) was successfully prepared using quench cooling. The formed co-amorphous material (namely CUR-CHA CM) eliminated the gelation and hence performed superior dissolution performance than crystalline/amorphous CUR. Meanwhile, it exhibited higher physical stability than amorphous CUR during dissolution as well as under long-term/accelerated conditions. To further study the such enhancement mechanism, the internal molecular interactions were investigated for CUR-CHA CM in the solid state as well as in aqueous solution. FTIR and solid-state 13C NMR spectra confirmed that intermolecular hydrogen bonds formed between CUR and CHA after co-amorphization. Furthermore, the nucleation of CUR was significantly inhibited by CHA in an aqueous solution, thus maintaining the supersaturated dissolution for a long time. The present study offers a feasible strategy to eliminate gelation and enhance stability of amorphous solids by co-amorphization and crystallization inhibition.

Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery.

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pKa = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 µg/mL at pH 1-6.8, dose number of 1.31 × 104), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

Hot Melt Extrusion-Triggered Amorphization as a Continuous Process for Inducing Extended Supersaturable Drug Immediate-Release from saSMSDs Systems.

Hot melt extrusion (HME), a continuous manufacturing process for generating supersaturating amorphous self-micellizing solid dispersion systems (saSMSDs), holds promise for achieving amorphization of many pharmaceutical formulations. For saSMSDs generation, HME-triggered continuous processes offer advantages over traditional non-continuous processes such as fusion/quench cooling (FQC) and co-precipitation (CP). Here we employed HME, FQC, and CP to generate saSMSDs containing the water-insoluble BCS II drug nitrendipine (NIT) and self-micellizing polymer Soluplus®. Scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry results revealed that saSMSDs formed when NIT-Soluplus® mixtures were subjected to the abovementioned amorphization methods. All saSMSDs outperformed crystalline NIT preparations and physical mixtures in achieving extended supersaturable immediate release states with superior solubility, "spring-parachute" process characteristics, and dissolution behaviors. Notably, Fourier transform-infrared spectroscopic results obtained for saSMSDs detected hydrogen bonding interactions between the drug and the carrier. Ultimately, our results revealed the advantages of HME-triggered amorphization as a continuous process for significantly improving drug dissolution, increasing solubility, and maintaining supersaturation as compared to traditional amorphization-based techniques.

Downregulation of inflammatory mediators by ethanolic extract of Bergenia ligulata (Wall.) in oxalate injured renal epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: In the Indian traditional system of medicine, Bergenia ligulata (Wall.) Engl. has been used for treatment of urolithiasis. Its efficacious nature has led to its incorporation in various commercial herbal formulations such as Cystone and Neeri which are prescribed for kidney related ailments. AIM OF THE STUDY: To assess whether ethanolic extract of B. ligulata can mitigate the cascade of inflammatory responses that cause oxidative stress and ultimately cell death in renal epithelial cells exposed to hyperoxaluric conditions. MATERIAL AND METHODS: Bioactivity guided fractionation using solvents of varying polarities was employed to evaluate the potential of the extracts of B. ligulata to inhibit the crystallization process. Modulation of crystal morphology was visualized through Scanning electron microscopy (SEM) analysis. Cell death was assessed using flow cytometry based assays. Alteration in the inflammatory mediators was evaluated using real time PCR and immunocytochemistry. Phytochemical characterization of the ethanolic extract was carried out using FTIR, LC-MS and GC-MS. RESULTS: Bioactivity guided fractionation for the assessment of antilithiatic activity revealed dose dependent inhibition of nucleation and aggregation process of calcium oxalate crystals in the presence of various extracts, however ethanolic extract showed maximum inhibition and was chosen for further experiments. Studies on renal epithelial NRK-52E cells showed, cytoprotective efficacy of B. ligulata extract against oxalate injury. SEM anaysis further revealed the potential of the extract to modulate the crystal structure and adhesion to renal cell surface. Exposure of the renal cells to the extract led to conversion of the calcium oxalate monohydrate (COM) crystals to the less injurious calcium oxalate dihydrate (COD) form. Expression analysis for oxidative stress and inflammatory biomarkers in NRK-52E cells revealed up-regulation of Mitogen activated protein kinase (MAPK), Osteopontin (OPN) and Nuclear factor- ĸB (NF-ĸB), in response to calcium oxalate insult; which was drastically reduced in the presence of B. ligulata extract. Flow cytometric evaluation pointed to caspase 3 mediated apoptotic cell death in oxalate injured cells, which was attenuated by B. ligulata extract. CONCLUSION: Considering the complex multifactorial etiology of urolithiasis, ethanolic extract from B. ligulata can be a promising option for the management of kidney stones, as it has the potential to limit inflammation and the subsequent cell death.

Molecular basis of ice-binding and cryopreservation activities of type III antifreeze proteins.

Antifreeze proteins (AFPs) can inhibit the freezing of body fluid at subzero temperatures to promote the survival of various organisms living in polar regions. Type III AFPs are categorized into three subgroups, QAE1, QAE2, and SP isoforms, based on differences in their isoelectric points. We determined the thermal hysteresis (TH), ice recrystallization inhibition (IRI), and cryopreservation activity of three isoforms of the notched-fin eelpout AFP and their mutant constructs and characterized their structural and dynamic features using NMR. The QAE1 isoform is the most active among the three classes of III AFP isoforms, and the mutants of inactive QAE2 and SP isoforms, QAE2ACT and SPACT, displayed the full TH and IRI activities with resepect to QAE1 isoform. Cryopreservation studies using mouse ovarian tissue revealed that the QAE1 isoform and the active mutants, QAE2ACT and SPACT, more effectively preserved intact follicle morphology and prevented DNA double-strand break damage more efficiently than the inactive isoforms. It was also found that all active AFPs, QAE1, QAE2ACT, and SPACT, formed unique H-bonds with the first 310 helix, an interaction that plays an important role in the formation of anchored clathrate water networks for efficient binding to the primary prism and pyramidal planes of ice crystals, which was disrupted in the inactive isoforms. Our studies provide valuable insights into the molecular mechanism of the TH and IRI activity, as well as the cryopreservation efficiency, of type III AFPs.

Porphyra yezoensis polysaccharide and potassium citrate synergistically inhibit calcium oxalate crystallization induced by renal epithelial cells and cytotoxicity of the formed crystals.

Mineralization crystallization is considered to be the initial stage of stone formation. However, the formation of crystals and subsequent cell damage have rarely been investigated. An oxidatively damaged cell model was established using oxalic acid to injure human proximal tubular epithelial cells (HK-2). Subsequently, CaOx crystallization was induced by adding 2.0 mmol/L sodium oxalate solution. We compared the synergistic effects of PYPs with molecular weights of 49.54 kDa (PYP1) and 4.02 kDa (PYP2) and K3Cit on the inhibition of CaOx crystallization and studied the nucleation, growth, and retention process of CaOx crystals on the cell surface and the subsequent damage of the formed crystals to the cells. Normal HK-2 cells mainly induced the formation of CaOx dihydrate (COD), whereas the damaged cells mainly induced the formation of CaOx monohydrate (COM) crystals. Under the protection of PYPs, the state of cells was improved, and the proportion of COD crystals in the formed crystals increased. Small-molecular-weight PYP2 exhibited better abilities of inhibiting CaOx crystallization and improving cell state compared with PYP1. Under the synergistic effects of PYPs and K3Cit, the number of formed crystals was obviously reduced, and the size was obviously decreased. PYPs can repair damaged cells and inhibit the conversion of COD phase to COM phase. K3Cit can obviously inhibit the nucleation of CaOx crystal and reduce the amount of crystal formation. The repair of damaged cells by PYPs and the synergistic inhibition of CaOx crystallization by PYPs and K3Cit reduce cell damage and crystal formation on the cell surface. By simultaneously repairing damaged cells and inhibiting crystallization, this strategy is expected to exert a desirable effect in preventing the formation and recurrence of stones.

Engineered Hydrophobin as a Crystallization Inhibitor for Flufenamic Acid.

Hydrophobins are multifunctional, highly surface-active proteins produced in filamentous fungi. Due to their surface-active properties, resistance to degradation, and potential immunological inertness, hydrophobins have been used in many applications such as protein purification, increasing implant biocompatibility, increasing water solubility of insoluble drugs, and foam stabilizers for food products. To further explore surface-active and self-assembly properties of hydrophobins, we evaluated an engineered, recombinant hydrophobin (class II type 1, HFB1) as a potential crystallization inhibitor for maintaining drug supersaturation for an amorphous drug delivery system. A supersaturation-precipitation method was employed utilizing an ultraviolet (UV) fiber optic system for tracking precipitation kinetics of a model drug, flufenamic acid (FA), that was selected due to its low aqueous solubility in its crystalline form. The effectiveness of HFB1 as a crystallization inhibitor was compared with commonly used pharmaceutical grade polymeric crystallization inhibitors. The following polymers were selected to compare with HFB1: methocel (A4C grade), methocel (K15M grade), Kollidon vinylpyrrolidone-vinyl acetate (VA64), and hydroxypropyl methylcellulose acetate succinate (HPMCAS) (MF grade). The supersaturation-precipitation experiments concluded that HFB1 outperformed all polymers tested in this study and can potentially be used as a crystallization inhibitor at significantly lower concentrations in amorphous drug delivery systems. Dynamic light scattering (DLS) and circular dichroism (CD) results suggest a crystallization inhibition mechanism in which HFB1 functions differently depending on whether flufenamic acid is molecularly dispersed but supersaturated relative to its crystalline solubility or it has exceeded its amorphous solubility limit and exists as a phase-separated drug-rich colloid.

Forming amorphous calcium carbonate within hydrogels by enzyme-induced mineralization in the presence of N-(phosphonomethyl)glycine.

Amorphous inorganic materials have a great potential in material science. Amorphous calcium carbonate (ACC) is a widely useable system, however, its stabilization often turns out to be difficult and the synthesis is mostly limited to precipitation in solution as nanoparticles. Stable ACC in bulk phases would create new composite materials. Previous work described the enzyme-induced mineralization of hydrogels with crystalline calcium carbonate by entrapping urease into a hydrogel and treating this with an aqueous mineralization solution containing urea und calcium chloride. Here, this method was modified using a variety of crystallization inhibitors attached to the hydrogel matrix or added to the surrounding mineralization solution. It was found that only N-(phosphonomethyl)glycine (PMGly) in solution completely inhibits the crystallization of ACC in the hydrogel matrix. The stability of the homogeneously precipitated ACC could be accounted to the combination of stabilizing effects of the additive and stabilization through confinement. The crystallization could be accelerated at higher temperatures up to 60 °C. Here, a combination of Mg ions and PMGly was required to stabilize ACC in the hydrogel. Variation of these two compounds can be used to control a number of different calcium carbonate morphologies within the hydrogel. While the ACC nanoparticles within the hydrogel are stable over weeks even in water, a calcite layer grows on the surface of the hydrogel, which might be used as self-hardening mechanism of a surface.

The tangential flow absorption model (TFAM) - A novel dissolution method for evaluating the performance of amorphous solid dispersions of poorly water-soluble actives.

There is a substantial demand for absorptive dissolution tests, as single vessel dissolution experiments were originally not designed for testing supersaturating systems. Current approaches suffer from inadequate mass transfer of the dissolved active from the dissolution site, discrepancies in the fluid volume compared to in vivo intestinal fluid volumes or the dilution of functional excipients. In this work a novel dissolution apparatus was developed that enables adjustable mass transfer of the active through a membrane, while retaining the functional polymeric excipients at the dissolution site. Using this setup the dissolution behavior of various spray dried amorphous solid dispersions containing carbamazepine, hydrochlorothiazide and ketoconazole as model actives at intermediate and high supersaturation levels was evaluated. Compared to non-absorptive dissolution experiments, differences in the concentration-time profiles were noted. The experiments with a high supersaturation of ketoconazole revealed a concentration decrease over time under absorptive conditions. Additionally, it was observed that the difference between "spring" as well as "spring and parachute" formulations was less pronounced with increasing drug efflux. Further, the apparatus was also tested with Fasted State Simulated Intestinal Fluid as dissolution medium and results were compared to phosphate buffer pH6.8. As major benefits of the new TFAM apparatus the easy experimental procedure and sample preparation for drug concentration measurements using spectroscopy in the permeate, without the necessity for additional filtration and/or centrifugation to remove precipitated drug molecules, could be highlighted. This TFAM approach seems to be a promising tool for identifying formulations for amorphous solid dispersions with optimal in vitro performance.

The use of amphiphilic copolymer in the solid dispersion formulation of nimodipine to inhibit drug crystallization in the release media: Combining nano-drug delivery system with solid preparations.

Solid dispersion is a widely used method to improve the dissolution and oral bioavailability of water-insoluble drugs. However, due to the strong hydrophobicity, the drug crystallization in the release media after drug dissolution and the resulted decreased drug absorption retards the use of solid dispersions. It is widely known that the amphiphilic copolymer can encapsulate the hydrophobic compounds and help form stable nano-dispersions in water. Inspired by this, we tried to formulate the solid dispersion of nimodipine by using amphipathic copolymer as one of the carriers. Concerning the solid dispersions, there are many important points involved in these formulations, such as the miscibility between the drug and the carriers, the storage stability of solid dispersions, the dissolution enhancement and so on. In this study, a systemic method is proposed. In details, the supersaturation test and the glass transition temperature (Tg) measurement to predict the crystallization inhibition, the ratios of different components and the storage stability, the interactions among the components were investigated in detail by nuclear magnetic resonance (1H NMR) and isothermal titration calorimetry (ITC) and, the final dissolution and oral bioavailability enhancement. It was found that the amphiphilic copolymer used in the solid dispersion encouraged the formation the drug loading micelles in the release media and, finally, the problem of drug crystallization in the dissolution process was successfully solved.

Dicarboxylic acid as a linker to improve the content of amorphous drug in drug-in-polymer film: Effects of molecular mobility, electrical conductivity and intermolecular interactions.

Amorphous solid dispersion (ASD) is a well-established approach to improve the dissolution rate of the drugs with low water solubility. However, the application of the ASD was hindered by the low drug content and high risk of re-crystallization of drugs. The purpose of this research was to develop an ASD film with high content of amorphous olanzapine (OLN) for oral delivery. To overcome the high crystallization tendency of OLN in polyvinyl alcohol (PVA) films, three dicarboxylic acids (succinic acid (Suc), fumaric acid (Fum) and malic acid (Mal)) were introduced in the drug-in-polymer system as linkers between the drug and the polymer. The influence of the linkers on the re-crystallization of OLN in PVA films was evaluated by polarized light microscopy (PLM) and x-ray diffraction (XRD). Then, the possible mechanisms of crystallization inhibition were discussed based on the results of dielectric spectroscopy (DES), differential scanning calorimetry (DSC), attenuated total reflectance Fourier transform infrared (ATR-FTIR), Raman spectroscopy and molecular modeling. Finally, the effect of the linkers on the in vitro dissolution of the OLN-in-PVA films was studied in simulant saliva, and the in vivo performance of the optimal formulation was evaluated in rats. The results showed that OLN-in-PVA film have lower molecular mobility, lower electrical conductivity and stronger intermolecular interactions with the existence of Mal, which led to a better crystallization inhibition of OLN in PVA films. The re-crystallization of OLN in PVA films decreased the dissolution rate of OLN in simulant saliva. The in vivo performance of the optimal formulation was similar with that of OLN solution in rats. This study introduced a novel strategy to reduce the risk of drug re-crystallization in ASD, and also provided a deeper insight into the mechanisms of crystallization inhibition in ASD. The results will improve the judicious selection of excipients in pharmaceutical formulations.

Inhibiting or Accelerating Crystallization of Pharmaceuticals by Manipulating Polymer Solubility.

Polymers play a central role in controlling the crystallization of pharmaceuticals with effects as divergent as amorphous form stabilization and the acceleration of crystallization. Here, using pyrazinamide and hydrochlorothiazide as model pharmaceuticals, it is demonstrated that the same functional group interactions are responsible for these opposing behaviors and that whether a polymer speeds or slows a crystallization can be controlled by polymer solubility. This concept is applied for the discovery of polymers to maintain drug supersaturation in solution: the strength of functional group interactions between drug and polymer is assessed through polymer-induced heteronucleation, and soluble polymers containing the strongest-interacting functional groups with drug are shown to succeed as precipitation inhibitors.