Drug-Polymer Miscibility and the Overlap Concentration (C*) as Measured by Rheology: Variation of Polymer Structure.

OBJECTIVES: Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction. METHODS: We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf  and by X-ray diffraction. RESULTS: We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*. CONCLUSIONS: Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers.

Biodegradable Elastomers Enabling Thermoprocessing Below 100 °C.

Biodegradable and biocompatible elastomers are highly desirable for many biomedical applications. Here, we report synthesis and characterization of poly(ε-caprolactone)-co-poly(ß-methyl-δ-valerolactone)-co-poly(ε-caprolactone) (PCL-PßMδVL-PCL) elastomers. These materials have strain to failure values greater than 1000%. Tensile set measurements according to an ASTM standard revealed a 98.24% strain recovery 10 min after the force was removed and complete strain recovery 40 min after the force was removed. The PßMδVL midblock is amorphous with a glass-transition temperature of -51 °C, and PCL end blocks are semicrystalline and have a melting temperature in the range of 52-55 °C. Due to their thermoplastic nature and the low melting temperature, these elastomers can be readily processed by printing, extrusion, or hot-pressing at 60 °C. Lysozyme, a model bioactive agent, was incorporated into a PCL-PßMδVL-PCL elastomer through melt blending in an extruder, and the blend was further hot-pressed into films; both processing steps were performed at 60 °C. No loss of lysozyme bioactivity was observed. PCL-PßMδVL-PCL elastomers are as cytocompatible as tissue culture polystyrene in supporting cell viability and cell growth, and they are degradable in aqueous environments through hydrolysis. The degradable, cytocompatible, elastomeric, and thermoplastic properties of PCL-PßMδVL-PCL polymers collectively render them potentially valuable for many applications in the biomedical field, such as medical devices and tissue engineering scaffolds.

Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*).

Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a "sphere of influence" of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C* is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C* in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔHf), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔHf/ΔHf,C=0 = f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼Tg + 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C* in selecting polymer concentrations when formulating drugs as ASDs.

Challenges in Transitioning Cocrystals from Bench to Bedside: Dissociation in Prototype Drug Product Environment.

Tablets containing a theophylline-glutaric acid (TG) cocrystal dissociated rapidly forming crystalline theophylline (20-30%), following storage at 40 °C/75% RH for 2 weeks. Control tablets of TG cocrystal containing no excipients were stable under the same conditions. The dissociation reaction was water-mediated, and the theophylline concentration (the dissociation product), monitored by synchrotron X-ray diffractometry, was strongly influenced by the formulation composition. Investigation of the binary compacts of the TG cocrystal with each excipient revealed the influence of excipient properties (hydrophilicity, ionizability) on cocrystal stability, providing mechanistic insights into a dissociation reaction. Ionizable excipients with a strong tendency to sorb water, for example, sodium starch glycolate and croscarmellose sodium, caused pronounced dissociation. Microcrystalline cellulose (MCC), while a neutral but hydrophilic excipient, also enabled solution-mediated cocrystal dissociation in intact tablets. Magnesium stearate, an ionizable but hydrophobic excipient, interacted with the cocrystal to form a hygroscopic product. The interaction is believed to be initiated in the disordered cocrystal-excipient particle interface. In contrast, the cocrystal was stable in the presence of lactose, a neutral excipient with no tendency to sorb water. The risk of unintended cocrystal dissociation can be mitigated by avoiding contact with water both during processing and storage.

Cellulose nanocrystal effect on crystallization kinetics and biological properties of electrospun polycaprolactone.

Mechanical properties of tissue engineering nanofibrous scaffolds are of importance because they not only determine their ease of application, but also influence the environment for cell growth and proliferation. Cellulose nanocrystals (CNCs) are natural renewable nanoparticles that have been widely used for manipulating nanofibers' mechanical properties. In this article, cellulose nanoparticles were incorporated into poly(caprolactone) (PCL) solution, and composite nanofibers were produced. Ozawa-Flynn-Wall (OFW) methodology and X-ray diffraction were used to investigate the effect of CNC incorporation on PCL crystalline structure and its biological properties. Results showed that CNC incorporation up to 1% increases the crystallization activation energy and reduces the crystal volume, while these factors remain constant above this critical concentration. MTT assay and microscopic images of seeded cells on the nanofiber scaffolds indicated increased cell growth on the samples containing CNC. This behavior could be attributed to their greater hydrophilicity, which was confirmed using parallel exponential kinetics (PEK) model fitting to results obtained from dynamic vapor sorption (DVS) studies. Superior performance of CNC containing samples was also confirmed by in vivo implantation on full-thickness wounds. The wound area faded away more rapidly in these samples. H&E and Masson's trichrome staining showed better regeneration and more developed tissues in wounds treated with PCL-CNC1% nanofibers.

Towards development of selective and reversible pyrazoline based MAO-inhibitors: Synthesis, biological evaluation and docking studies.

Ten novel 3,5-diaryl pyrazolines were synthesized and investigated for their monoamine oxidase (MAO) inhibitory property. All the molecules were found to be reversible and selective inhibitor for either one of the isoform (MAO-A or MAO-B). Further insights in the theoretical evaluation of the possible interactions between the compounds and monoamine oxidases (MAO-A or MAO-B) have been developed through docking studies. The theoretical values are in congruence with their experimental values.

Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability.

Influence of crosslinking (crosslinker concentration and crosslinking condition) on molecular mobility and physical stability of ketoconazole (KTZ) solid dispersions was investigated over a wide temperature range in the supercooled state. Amorphous solid dispersions (ASDs) with very high drug loading (95% w/w) were prepared by thermal crosslinking. As the crosslinker concentration increased (from 0.25-1.0% w/w), there was a progressive decrease in molecular mobility as evident from both the longer α-relaxation time, and higher viscosity values. Consequently, there was progressive enhancement in physical stability (crystallization inhibition). At 1.0% w/w crosslinker concentration, when compared with the drug alone, there was ~4 orders of magnitude increase in both viscosity and α-relaxation times. Elevating the crosslinking temperature, by increasing the crosslinking density, provided a second avenue to enhance physical stability. Hence, crosslinking density offers a simple method to enhance physical stability and control drug release. We have formulated ASDs: (i) with very high drug loading (95% w/w), and (ii) pronounced stability even when exposed to elevated temperatures and water vapor pressure. Also, during dissolution study, the degree of supersaturation in the dissolution medium generated by the crosslinked systems gradually increased and maintained the supersaturation for a longer period.