Stacey T. Long

Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability.

AbstractPurpose. To investigate the effect of vitamin E-TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate, on the solubility and permeability of amprenavir, a potent HIV protease inhibitor. Methods. The aqueous solubility of amprenavir was measured as a function of vitamin E-TPGS concentration. Directional transport through Caco-2 cell monolayers was determined in the presence and absence of vitamin E-TPGS and P-glycoprotein inhibitors. Absorption flux was estimated from Caco-2 cell permeability and aqueous solubility. Results. The solubility of amprenavir in a pH 7 buffer at 37°C was 0.036 ± 0.007 mg/mL. The solubility linearly increased with increasing vitamin E-TPGS concentration (above 0.2 mg/mL). Polarized transport was demonstrated in the basolateral to apical direction, exceeding apical to basolateral transport by a factor of 6. The active efflux system was inhibited by vitamin E-TPGS and known P-glycoprotein inhibitors verapamil and GF120918. Conclusions. The solubility of amprenavir was improved in the presence of vitamin E-TPGS through micelle solubilization. Vitamin E-TPGS inhibits the efflux system and enhances the permeability of amprenavir. Overall, vitamin E-TPGS enhanced the absorption flux of amprenavir by increasing its solubility and permeability. The enhancement is essential to the development of the novel soft gelatin capsule formulation of amprenavir for use in the clinic.

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: Crystal structures and multinuclear solid-state NMR

Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.

Excipient compatibility as assessed by isothermal microcalorimetry

Pharmaceutical development has always been faced with the challenge of rapidly developing formulations exhibiting long-term stability and bioavailability without the benefit of supporting long term data at normal storage conditions. Drug-excipient compatibility assessments are therefore carried out over shorter time intervals (typically weeks to months) at elevated temperatures in order to predict long term stability at ambient conditions. Traditionally, analyses of stressed samples are most often performed by HPLC in which the decrease in the parent peak and/or increases in degradation peaks are monitored. Ideally, these analyses should be validated for every excipient and degradant encountered. This is generally time consuming and often not very practical at the early stages of development. Expeditious excipient compatibility screening is a formidable challenge confronting every major pharmaceutical company. Because of the fast, highly competitive pace of development processes today, more traditional screening techniques are often inadequate in terms of timeliness and reliability. The application of microcalorimetry to excipient compatibility screening can potentially provide substantial payback by providing by more timely and reliable data. The purpose of this work was to develop and evaluate an isothermal calorimetric method for predicting drug-excipient compatibility. In order to ensure thorough and intimate mixing of the drug and excipient, mixtures were prepared by mix/ milling components in a vibratory ball mill (1:l binary mixtures). Individual component and mixture particle size reduction and distribution were assessed by Malvern analysis. Samples were calorimetrically examined in glass crimp-top vials using a Thermometric 2277 TAM microcalorimeter at 50C under fixed relative humidity. Data were collected over a 15 hour time interval after 1 to 4 days equilibration time. A theoretical heat flow for no interaction is calculated from the heat flow of the individual mixture components and compared to the actual heat flow for the mixture. A weighted compatibility factor is then calculated from the calorimetry data as a means of assessing mixture compatibility. Results are compared to similar samples examined by HPLC analysis after longer term storage. As an example of this technique, data are presented for a new drug (NCE) currently under development, with a range of excipients. A basic premise for the microcalorimetric analyses is that milling the mixture components individually results in approximately the same particle size distribution as milling mixture components together. From the limited number of components analysed, the authors are satisfied that this is a fair, but not perfect assumption in this approach to excipient compatibility screening. The NCE-excipient Samples showed very good reproducibility in signal output and calculated compatibility factors. In general, the calorimetric data compared well to HPLC analyses of similar samples after longer term storage. With mixtures containing a hygroscopic excipient, the no interaction heat flow calculated by this technique may not be appropriately compared to the actual mixture (e.g. NCE-sodium starch glycolate, mannitol-sodium starch glycolate). In conclusion, a useful method for screening drug-excipient compatibility by microcalorimetry was developed. In a relatively short time-frame, this technique can provide the formulator with meaningful data by which sensible decisions can be made with respect to the choice of excipients to use. However, the reliability of this method for mixtures containing hygroscopic components is currently unresolved.

The Degradation Chemistry of Farglitazar and Elucidation of the Oxidative Degradation Mechanisms

The chemical degradation of farglitazar (1) was investigated using a series of controlled stress testing experiments. Farglitazar drug substance was stressed under acidic, natural pH, basic, and oxidative conditions in solution. In the solid state, the drug substance was stressed with heat, high humidity, and light. Farglitazar was found to be most labile toward oxidative stress. A series of mechanistic experiments are described in which the use of 18O-labelled oxygen demonstrated that oxidative degradation of farglitazar is caused primarily by singlet oxygen formed under thermal conditions. Major degradation products were isolated and fully characterized. Mechanisms for the formation of degradation products are proposed. Drug product tablets were also stressed in the solid state with heat, high humidity, and light. Stressed tablets afforded many of the same degradation products observed during drug substance stress testing, with oxidation again being the predominant degradation pathway. Evidence for the activity of singlet oxygen, formed during thermal stress testing of the solid oral dosage form, is presented. The degradation pathways observed during stress testing matched those observed during long-term stability trials of the drug product.