Preparation, structural analysis, and properties of tenoxicam cocrystals.

Cocrystals of tenoxicam, a non-steroidal anti-inflammatory drug, are screened, prepared, and characterized in this study. Nine tenoxicam cocrystals were identified using solvent-drop grinding (SDG) techniques. Structural characterization was performed using powder X-ray diffraction (PXRD), differential scanning calorimetry, and multinuclear solid-state NMR (SSNMR). Thermal analysis, PXRD, and 1D SSNMR are used to detect solvates and phase mixtures encountered in SDG cocrystal screening. 2D SSNMR methods are then used to confirm cocrystal formation and determine structural aspects for selected cocrystals formed with saccharin, salicylic acid, succinic acid, and glycolic acid in comparison to Forms I and III of tenoxicam. Molecular association is demonstrated using cross-polarization heteronuclear dipolar correlation (CP-HETCOR) methods involving (1)H and (13)C nuclei. Short-range (1)H-(13)C CP-HETCOR and (1)H-(1)H double-quantum interactions between atoms of interest, including those engaged in hydrogen bonding, are used to reveal local aspects of the cocrystal structure. (15)N SSNMR is used to assess ionization state and the potential for zwitterionization in the selected cocrystals. The tenoxicam saccharin cocrystal was found to be similar in structure to a previously-reported cocrystal of piroxicam and saccharin. The four selected cocrystals yielded intrinsic dissolution rates that were similar or reduced relative to tenoxicam Form III.

Preparation and structural characterization of amorphous spray-dried dispersions of tenoxicam with enhanced dissolution.

Tenoxicam is a poorly soluble nonsteroidal anti-inflammatory drug. In this work, the solubility of tenoxicam is enhanced using amorphous spray-dried dispersions (SDDs) prepared using two molar equivalents of l-arginine and optionally with 10%-50% (w/w) polyvinylpyrrolidone (PVP). When added to the dispersions, PVP is shown to improve physical properties and also assists in maintaining supersaturation in solution. The dispersions provide a twofold increase over equilibrium solubility at the same pH. The dispersions are characterized using electron microscopy, vibrational spectroscopy, diffuse-reflectance visible spectroscopy, and X-ray powder diffraction. The structures of the dispersions are probed using solid-state nuclear magnetic resonance (SSNMR) experiments applied to the (1) H, (13) C, and (15) N nuclei, including two-dimensional dipolar correlation experiments that detect molecular association and the formation of a glass solution between tenoxicam, l-arginine, and PVP. Other aspects of the amorphous structure, including hydrogen-bonding interactions and the ionization state of tenoxicam and l-arginine, are also explored using SSNMR methods. These methods are used to show that the SDDs contain an amorphous l-arginine salt of tenoxicam in a glass solution that also includes PVP when present. Finally, the dispersions show only a minor decrease in chemical stability during accelerated stability studies relative to a crystalline form of tenoxicam.

Solubility and partitioning of carbamazepine in a two-phase supercritical carbon dioxide/polyvinylpyrrolidone system.

Supercritical carbon dioxide (scCO(2)) processing of drug/polymer mixtures is an environmentally friendly means of creating an impregnated polymeric carrier to enhance the aqueous dissolution rate of drugs that exhibit poor water solubility or are thermally labile. However, the role of drug solubilization and its interaction with the polymer during scCO(2) processing on the extent and rate of dissolution has been ambiguous. In this study, we examine the rate of dissolution of carbamazepine (CBZ), a hydrophobic drug for treating epilepsy, in scCO(2) (90-200bar, 35°C and 45°C) and its partitioning into polyvinylpyrrolidone (PVP, 10 and 29K MW) using in situ UV-vis spectroscopy. Our results show that partitioning occurs by surface adsorption and impregnation within the polymer matrix. These processes are linked to plasticization, which is dependent on PVP molecular weight, and temperature and pressure during treatment. The rate and extent of CBZ solubility is also controlled by treatment condition. The ability to tune polymer and drug simultaneously can be used to control the nature and extent of drug loading.

Effect of n-scCO(2) on crystalline to amorphous conversion of carbamazepine.

A number of studies have been carried out to investigate the crystalline to amorphous conversion of carbamazepine (CBZ) using solid dispersion techniques. In this study we have tried to achieve conversion using a novel technique combining near-supercritical carbon dioxide (n-scCO(2)) and pharmaceutically acceptable polymers (Na CMC and PVP) of varying molecular weights. Physical mixtures were prepared in two identical sets, one exposed to n-scCO(2) treatment and other was untreated. The treated physical mixtures were compared to untreated using PXRD, DSC and USP in vitro dissolution techniques. Routinely used PXRD analysis involves qualitative estimation of the amorphous conversion of a drug. In this work a previously developed mathematical parameter, ratio of ratios (ROR), was utilized to better quantify the crystalline to amorphous conversion of CBZ. The findings from the three methods indicated that only the lowest molecular weight PVP, PVP10k, facilitated significant crystalline to amorphous conversion of CBZ. In vitro dissolution, which is considered as an estimate of bioavailability demonstrated an initial dissolution of CBZ significantly greater in the treated physical mixtures of PVP10k:CBZ than the initial dissolution of the corresponding untreated physical mixtures and pure untreated CBZ.

Design and process aspects of laboratory scale SCF particle formation systems.

Consistent production of solid drug materials of desired particle and crystallographic morphologies under cGMP conditions is a frequent challenge to pharmaceutical researchers. Supercritical fluid (SCF) technology gained significant attention in pharmaceutical research by not only showing a promise in this regard but also accommodating the principles of green chemistry. Given that this technology attained commercialization in coffee decaffeination and in the extraction of hops and other essential oils, a majority of the off-the-shelf SCF instrumentation is designed for extraction purposes. Only a selective few vendors appear to be in the early stages of manufacturing equipment designed for particle formation. The scarcity of information on the design and process engineering of laboratory scale equipment is recognized as a significant shortcoming to the technological progress. The purpose of this article is therefore to provide the information and resources necessary for startup research involving particle formation using supercritical fluids. The various stages of particle formation by supercritical fluid processing can be broadly classified into delivery, reaction, pre-expansion, expansion and collection. The importance of each of these processes in tailoring the particle morphology is discussed in this article along with presenting various alternatives to perform these operations.

Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement.

Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the permeation constant, while the values of lag time were reversed. The ternary mixture was then selected as a potential absorption enhancement vehicle for the transdermal delivery of drug. In general, higher fluxes were observed through hairless guinea pig skin as compared with the human stratum corneum. Based on the results obtained from the release study of NC-HCl from saturated solutions of the drug, a novel lecithin organogel (microemulsion-based gel) composed of soybean lecithin, propylene glycol, oleic acid, dimethyl isosorbide, and isopropyl myristate was developed as a possible matrix for transdermal delivery of NC-HCl. In vitro percutaneous penetration studies from this newly developed gel system through giunea pig skin and human stratum corneum revealed that the organogel system has skin-enhancing potential and could be a promising matrix for the transdermal delivery of nicardipine. Furthermore, higher permeation rates were observed when nicardipine free base was incorporated into the gel matrix instead of hydrochloride salt.

Crystal doping aided by rapid expansion of supercritical solutions.

The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction ranged from 45 to 100 degrees C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies revealed the formation of eutectic mixtures and solid solutions of CPD + urea. Formation of the solid solutions resulted in the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these results were the reductions in melting point (up to 9 degrees C) and in the DeltaH(f) values of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional solvent-based cocrystallizations.