Polymer Nanocoating of Amorphous Drugs for Improving Stability, Dissolution, Powder Flow, and Tabletability: The Case of Chitosan-Coated Indomethacin.

As a result of its higher molecular mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissolution of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of physical stability, wetting by aqueous media, dissolution rate, powder flow, and tabletability. The coating condition was chosen so that the positively charged polymer deposits on the negatively charged drug. Chitosan coating is superior to gelatin coating with respect to stability against crystallization and agglomeration of coated particles.

Thermodynamics of water-solid interactions in crystalline and amorphous pharmaceutical materials.

Pharmaceutical materials, crystalline and amorphous, sorb water from the atmosphere, which affects critical factors in the development of drugs, such as the selection of drug substance crystal form, compatibility with excipients, dosage form selection, packaging, and product shelf-life. It is common practice to quantify the amount of water that a material sorbs at a given relative humidity (RH), but the results alone provide minimal to no physicochemical insight into water-solid interactions, without which pharmaceutical scientists cannot develop an understanding of their materials, so as to anticipate and circumvent potential problems. This research was conducted to advance the science of pharmaceutical materials by examining the thermodynamics of solids with sorbed water. The compounds studied include nonhygroscopic drugs, a channel hydrate drug, a stoichiometric hydrate excipient, and an amorphous excipient. The water sorption isotherms were measured over a range of temperature to extract the partial molar enthalpy and entropy of sorbed water as well as the same quantities for some of the solids. It was found that water-solid interactions spanned a range of energy and entropy as a function of RH, which was unique to the solid, and which could be valuable in identifying batch-to-batch differences and effects of processing in material performance.

Prediction of drug solubility in lipid mixtures from the individual ingredients.

The purpose of this research was to investigate the relationship of drug solubility in a complex lipid mixture to that of the individual ingredients with the goal of substantiating a quantitative equation that can be applied in formulation development of lipid dosage forms. To this end, the solubility of four drugs, which span a large range of physicochemical properties, was evaluated in 18 lipid ingredients that cover the major lipid classes. To assess the solubility relation in complex lipid mixtures in an unbiased manner, the experiments were created as an experimental design with the ability to detect cubic curvature in the solubility-lipid composition space. The results demonstrated that for all drugs, irrespective of their significantly distinct physicochemical properties, solubility in lipid mixtures can be readily estimated as a simple weighted average of the drug solubility in the individual ingredients. This result is of great value to formulators who can minimize a large number of solubility experiments once a basis set of solubility is determined in individual lipids.

Highly stable indomethacin glasses resist uptake of water vapor.

Mass uptake of water vapor was measured as a function of relative humidity for indomethacin glasses prepared using physical vapor deposition at different substrate temperatures. Highly stable glasses were produced on substrates at 265 K (0.84Tg) by depositing at 0.2 nm/s while samples similar to melt-cooled glasses were produced at 315 K and 5 nm/s. Samples deposited at 315 K absorb approximately the same amount of water as glasses prepared by supercooling the melt while stable glasses absorb a factor of 5 less water. Unexpectedly, the diffusion of water in the stable glass samples is 5-10 times faster than in the glass prepared by cooling the liquid.

Formulation development and process scale up of a high shear wet granulation formulation containing a poorly wettable drug.

Aplaviroc 200 mg tablets were made by a high shear wet granulation process. A formulation and process DOE were carried out to define formulation and process parameters at pilot scale in GSKs R&D facility. During the scale up, several batches made at the production facility dissolved slower than the R&D batches. Extensive studies were conducted to examine a variety of factors to identify the root cause of this small but consistent drop in dissolution. Tablet hardness and lubrication time had a rather surprising impact on drug dissolution. Softer tablets dissolved slower despite disintegrating faster. Lubricating the granules with magnesium stearate for 3 h produced faster dissolving tablets than lubricating the granules for 3 min. Visual observations made during the dissolution trials shed some light on these surprising phenomena. As tablets disintegrated, some fragments floated to the top of the dissolution vessels and remained floating throughout the test. Due to poor wetting and lack of shear force, the drug was entrapped in these floating particles. Softer tablets and "lightly-lubricated" tablets disintegrated faster and had the floating fragments appear earlier in the dissolution trial. Sourcing of magnesium stearate may also play a role on the floating behavior.

The nitrogen adsorption isotherm of alpha-lactose monohydrate.

A complete nitrogen adsorption isotherm was measured for alpha-lactose monohydrate, from 0.001 to 0.995 relative pressure at 77 K. The isotherm was qualitatively classified as Type II, and was quantitatively analyzed for surface area, porosity, and surface heterogeneity. Surface area results revealed that the normal Brunauer Emmett Teller (BET) range of 0.05-0.35 relative pressure was not suitable for this grade of lactose, but having full isotherm data enabled a more appropriate analytical range to be found, illustrating the importance of measuring the entire isotherm as an essential step in method development. The isotherm was analyzed for micro and mesoporosity, both of which were found to be insignificant for lactose. The low relative pressure range 0.001-0.005 did not obey Henry's law, indicating the presence of surface heterogeneity. Density functional theory was exploited to quantitatively measure heterogeneity in the surface energy of lactose, using the full nitrogen adsorption profile. As expected for a crystalline material with multiple faces and likely presence of imperfections on the surface, the surface energy distribution function was broad with more than one mode.

Solubilization and solid-state characterization of a poorly soluble 5-alpha reductase inhibitor.

GI197111X is a 5-alpha reductase inhibitor for the treatment of androgenetic alopecia. Equilibrium solubilities of GI197111X were determined in multiple solvents or cosolvents. A polymorph screen was conducted using suspension equilibration and solution recrystallization methods. Single crystals were grown from pyridine/water and crystal structure was determined using a Bruker SMART diffractometer. Crystal structure data were imported into Cerius2 to provide visualization of the crystal structure and calculation of the simulated X-ray powder diffraction (XRPD) pattern. The solubility of GI19711IX was low at 25 degrees C in all vehicles suitable for animal and human dosing. The solubility of 6.4 mg/mL in Capmul MCM made it the only choice for a soft gel dosage form for phase I/II. Solution recrystallization and suspension equilibration of GI197111X have produced only one crystal form. Crystal structure data: orthorhombic P2(1) 2(1) 2(1); a= 10.8960(6) A, b=11.5683(6) A, c=20.9019(11) A; unit cell volume 2634.65(24) A3; Z=4; calculated density= 1.248 g/cc. The molecule has seven chiral centers, and single-crystal analysis eliminated all possible stereo-isomers except the expected conformation or its enantiomer. Hydrogen bonds occur from both carbonyl oxygens to an H-N group. Simulated vacuum-based crystal morphology (habit) calculated using the Bravais-Friedel-Donnay-Harker, Growth Morphology, and Hartman-Perdok modules in Cerius2 was a close match to the morphology observed by light microscopy.

Determining the relative physical stability of anhydrous and hydrous crystal forms of GW2016.

The slurry equilibration method used to determine the relative physical stability of polymorphs is extended to a crystal system of an anhydrate and hydrate. The method involves preparation of organic/aqueous slurries of known water activity containing mixtures of the anhydrate and hydrate forms. The slurries equilibrate to the lowest free energy form, from which the relative physical stability is determined as a function of relative humidity. The method is particularly valuable when one or more of the crystal forms is kinetically stable, since solvent-mediated transformation accelerates the conversion process. Results are provided for GW2016 anhydrate and monohydrate crystal forms, for which it was determined that interconversion occurs between 7 and 15% relative humidity.

Solid state characterization of an neuromuscular blocking agent--GW280430A.

GW280430A is an ultrashort-acting neuromuscular blocking agent and is targeted for muscle relaxation as part of the intubation surgical procedure. The objective of this work was to perform solid state characterization on GW280430A and to evaluate the relationship between water content and glass transition temperature (Tg). GW280430A was characterized by differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction (PXRD), microscopy and moisture sorption. The effect of water content on the Tg of GW280430A was evaluated by equilibrating the material over saturated salt solutions at a range of relative humidities (6.4-72.6%) and determining the Tg by DSC using hermetically sealed aluminum pans. GW280430A undergoes dehydration at 40 degrees C, glass transition at 130 degrees C and decomposition at 190 degrees C by differential scanning calorimetry. By PXRD and moisture sorption, GW280430A is an amorphous material and deliquesces at about 70% RH at room temperature. Water acts as a potent plasticizer for GW280430A and the Tg decreases significantly as the water content increases. No measurable decomposition of GW280430A was observed after 4 weeks at 40 degrees C/75% RH.