In vitro-in vivo correlation for nevirapine extended release tablets.

An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time-scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles.

Prediction of onset of crystallization from experimental relaxation times. II. Comparison between predicted and experimental onset times.

UNLABELLED: Given a good correlation between onsets of crystallization and mobility above T(g), one might be able to predict crystallization onsets at a temperature of interest far below T(g) from this correlation and measurement of mobility at a temperature below T(g). Such predictions require that: (a) correlation between crystallization onset and mobility is the same above and below T(g), and (b) techniques used to measure mobility above and below T(g) measure the same kind of mobility [(b) demonstrated previously using dielectric and calorimetric techniques]. The objective of present work is to determine whether crystallization onset times couple with relaxation times determined above T(g), and if so to verify predictions made below T(g) (from data above T(g)) with experimental data. Model compounds were indomethacin, ketoconazole, flopropione, nifedipine, and felodipine. Onsets of crystallization measured above T(g) were coupled with dielectric mobility for indomethacin, felodipine, and flopropione. Prediction of crystallization onset times for temperatures below T(g) matched well with experimental data for indomethacin (25 degrees C, 35 degrees C: Predicted 473, 95 h; EXPERIMENTAL: 624 +/- 158, 139 +/- 49 h) and flopropione (35 degrees C, 40 degrees C; Predicted 115, 58 h; EXPERIMENTAL: 96 +/- 30, 59 +/- 10 h). The data suggests that coupling between crystallization onsets and molecular mobility at temperatures above T(g) may be exploited to develop stability testing protocol for crystallization from amorphous state.

Factors affecting the formation of eutectic solid dispersions and their dissolution behavior.

The objective of this work was to obtain a fundamental understanding of the factors, specifically the properties of poorly water-soluble drugs and water-soluble carriers, which influence predominantly, the formation of eutectic or monotectic crystalline solid dispersion and their dissolution behavior. A theoretical model was applied on five poorly water-soluble drugs (fenofibrate, flurbiprofen, griseofulvin, naproxen, and ibuprofen) having diverse physicochemical properties and water-soluble carrier (polyethylene glycol (PEG) 8000) for the evaluation of these factors. Of these, two drugs, fenofibrate and flurbiprofen, and PEG of different molecular weights (3350, 8000, and 20000), were chosen as model drugs and carriers for further investigation. Experimental phase diagrams were constructed and dissolution testing was performed to assess the performance of the systems. The theoretical model predicted the formation of eutectic or monotectic solid dispersions of fenofibrate, griseofulvin, ibuprofen, and naproxen with PEG, holding the contribution of specific intermolecular interactions between compound and carrier to zero. In the case of the flurbiprofen-PEG eutectic system, intermolecular interactions between drug and polymer needed to be taken into consideration to predict the experimental phase diagram. The results of the current work suggest that the thermodynamic function of melting point and heat of fusion (as a measure of crystal energy of drug) plays a significant role in the formation of a eutectic system. Lipophilicity of the compound (as represented by cLog P) was also demonstrated to have an effect. Specific interactions between drug and carrier play a significant role in influencing the eutectic composition. Molar volume of the drug did not seem to have an impact on eutectic formation. The polymer molecular weight appeared to have an impact on the eutectic composition for flurbiprofen, which exhibits specific interactions with PEG, whereas no such impact of polymer molecular weight on eutectic composition was observed for fenofibrate, which does not exhibit specific interactions with PEG. The impact of polymer molecular weight on dissolution of systems where specific drug-polymer interactions are exhibited was also observed. The current work provides valuable insight into factors affecting formation and dissolution of eutectic systems, which can facilitate the rational selection of suitable water-soluble carriers.

Properties of rapidly dissolving eutectic mixtures of poly(ethylene glycol) and fenofibrate: the eutectic microstructure.

Poly(ethylene glycol) or PEG is an ideal inactive component for preparing simple binary eutectic mixtures because of its low entropy of fusion ( approximately 0.0076 J/mol-K), lower melting point (approximately 62 degrees C) compared to most pharmaceuticals, miscibility with drugs at elevated temperatures, and its covalent crystalline lattice. Implication of these physicochemical properties on eutectic crystallization and size reduction of the drug is discussed. Enhancement of the dissolution rate of a poorly soluble compound through the formation of PEG-drug eutectics was investigated using fenofibrate. Solid dispersions of PEG-fenofibrate when characterized, revealed that PEG and fenofibrate form a simple eutectic mixture containing 20-25%(w/w) fenofibrate at the eutectic point. Eutectic crystallization led to the formation of an irregular microstructure in which fenofibrate crystals were found to be less than 10 microm in size. Dissolution rate improvement of fenofibrate correlated with the phase diagram, and the amount of fenofibrate released from the dispersions that contained fenofibrate as a eutectic mixture was at least 10-fold higher compared to untreated fenofibrate. On aging, the dissolution rate of the dispersion containing 15%(w/w) fenofibrate in PEG remained unaltered. The results indicate that PEG-drug eutectic formation is a valuable option for particle size reduction and subsequent dissolution rate improvement.

Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations.

Ritonavir is a large, lipophilic molecule that is practically insoluble in aqueous media and exhibits an exceedingly slow intrinsic dissolution rate. Although it has favorable lipophilicity, in vitro permeability studies have shown that ritonavir is a substrate of P-glycoprotein. Thus, the oral absorption of ritonavir could be limited by both dissolution and permeability, thereby making it a Class IV compound in the Biopharmaceutics Classification System. Because formulations rarely exert direct influence on local intestinal permeability, the effect of enhanced dissolution rate on oral absorption was explored. More specifically, poly(ethylene glycol) (PEG)-amorphous ritonavir solid dispersions were prepared with different drug loadings, and the in vitro and in vivo performances of the dispersions were evaluated. In vitro dissolution was conducted in 0.1N HCl with a USP Apparatus I. A crossover design was used to evaluate the oral bioavailability of amorphous dispersions relative to crystalline drug in beagle dogs. Intrinsic dissolution measurements of the two solid phases indicated a 10-fold improvement in intrinsic dissolution rate for amorphous ritonavir compared with the crystalline counterpart. In vitro dissolution of ritonavir depended on the solid phase as well as drug loading of the dispersion. In vivo study results indicate that amorphous solid dispersions containing 10-30% drug exhibited significant increases in area under the curve of concentration versus time (AUC) and maximum concentration (C(max)) over crystalline drug. For example, 10% amorphous dispersion exhibited increases of 22- and 13.7-fold in AUC and C(max), respectively. However, both in vitro dissolution and bioavailability decreased with increasing drug load, which led to the construction of a multiple Level C in vitro-in vivo relationship for this Class IV compound. The established relationship between in vitro dissolution and in vivo absorption can help guide formulation development.

Miscibility/stability considerations in binary solid dispersion systems composed of functional excipients towards the design of multi-component amorphous systems.

The correlations between amorphous miscibility/physical stability of binary solid dispersions (a highly crystalline additive-an amorphous polymer) and the physicochemical properties of the components were investigated. Crystalline functional excipients including surfactants, organic acids, and organic bases were prepared in binary solid dispersions in amorphous polymers by solvent evaporation method. Amorphous miscibility and physical stability of the systems were characterized using polarized light microscope, differential scanning calorimeter, and powder X-ray diffraction. Physicochemical parameters (solubility parameter (delta), hydrogen bond energy, Log P, pK(a) value as an indicator of acid-base ionic interaction, and T(g) of the dispersion as a surrogate of system's mobility) were selected as thermodynamic and kinetic factors to examine their influences on the systems' amorphous miscibility and physical stability. All systems possessing acid-base ionic interaction formed amorphous state. In the absence of the ionic interaction, solubility parameter and partition coefficient were shown to have major roles on amorphous formation. Upon storage condition at 25 degrees C/60% RH for 50 days, systems having ionic interaction and high T(g) remained in the amorphous state. This binary system study provides an insight and a basis for formation of the amorphous state of multi-component solid dispersions utilizing their physicochemical properties.

Drug-excipient complexation in lipid based delivery systems: an investigation of the Tipranavir-1,3-dioctanolyglycerol complex.

This report describes the solubility properties of a poorly soluble drug-excipient complex in a lipid based formulation. Tipranavir (TPV) was used as the model drug and 1,3-dioctanoylglycerol (DOG) as the excipient. The TPV-DOG complex was prepared by dissolving TPV and DOG in ethanol at 60 degrees C followed by evaporation of ethanol. The formation of the complex with a 4:1 TPV-to-DOG molar ratio was confirmed by XRPD, DSC, and NMR. At 25 degrees C, total solubility of TPV decreased with increasing DOG concentration. The solubility properties of the TPV-DOG complex can be described by two simultaneous equilibria: a liquid-solid phase equilibrium of the complex and a species equilibrium among the various species in the liquid phase. A model equation was derived accordingly with two parameters, the intrinsic solubility of the complex (S(o)), and the solution complex constant (K(41)). The model was in good agreement with experimental results. The values of S(o) and K(41) are 0.0186 +/- 0.0025 (M) and 21.97 +/- 7.19 (1/M(4)), respectively. The equation can successfully predict the concentrations of total and free TPV as a function of DOG in the formulation. The approach developed provides a useful tool for rationale selection of excipients and their levels to avoid drug precipitation in lipid based formulations.

Different measures of molecular mobility: comparison between calorimetric and thermally stimulated current relaxation times below Tg and correlation with dielectric relaxation times above Tg.

Stability of the amorphous state has been linked to molecular mobility of the matrix; however different techniques may capture different mobility substates. Our previous work suggested that two calorimetric techniques, Isothermal Microcalorimetry (TAM) and MDSC, measured different aspects of mobility with TAM measuring, in part, some faster modes of relaxation in addition to the modes mobilized at T(g). The aim of this work is to compare the relaxation times obtained using Thermally Stimulated Depolarization Current Spectroscopy (TSDC) with calorimetric mobility measured below T(g) and to determine if all measures of relaxation times below T(g) are consistent with relaxation times obtained above T(g) using Dielectric Spectroscopy (DRS). Model compounds were indomethacin, ketoconazole, nifedipine, flopropione, felodipine. For all compounds, relaxation times obtained using Thermal Windowing-TSDC technique below T(g) correlated well with relaxation times (tau) obtained above T(g) by DRS. At any given temperature below T(g), relaxation times measured depended upon the technique used and were in the following order TSDC < TAM < MDSC (tau). TSDC captures some faster relaxations not measured by calorimetric techniques, and therefore, different techniques give different measures of relaxation times below T(g). This information is important in understanding the relationships between mobility in the glassy solid and pharmaceutical stability.

Predictions of onset of crystallization from experimental relaxation times I-correlation of molecular mobility from temperatures above the glass transition to temperatures below the glass transition.

PURPOSE: Predicting onsets of crystallization at temperatures below T (g), from data above T (g), would require that the correlation between crystallization onset and mobility is same above and below T (g), and the techniques being used to measure mobility above and below T (g) are measuring essentially the same kind of mobility. The aim of this work is to determine if the relaxation times obtained using different techniques (DSC, TAM) below T (g) correlate with relaxation time obtained above T (g) using dielectric spectroscopy. METHODS: Model compounds for this work were chosen based on their varied DeltaH (f), DeltaC (p)(T (g)) and H-bonding in crystalline state vs. amorphous state. Relaxation times above T (g) were determined by the simultaneous fit of real and imaginary permittivity to the Cole-Davidson model. Tau and beta below T (g) were determined using isothermal microcalorimetry (TAM) or MDSC. MDSC was used to calculate Kauzmann temperature and strength of the glass using established relationships. RESULTS: Indomethacin, nifedipine and flopropione showed Arrhenius temperature dependence throughout the entire temperature range and extrapolation of tau ( beta ) measured above T (g) by dielectric relaxation agreed with tau ( beta ) measured below T (g) by TAM/MDSC. Ketoconazole, however, showed the expected VTF behavior. For at least two compounds compared (indomethacin and ketoconazole), relaxation times measured by TAM and MDSC did not agree, with TAM giving significantly lower values of tau ( beta ), but TAM and MDSC relaxation times appeared to extrapolate to a common value at T (g). CONCLUSIONS: It was found that, for all cases studied, relaxation time constants determined above and below T (g) did appear to extrapolate to the same value around T (g) indicating that molecular mobility measured above and below T (g) using different techniques is highly correlated.

A mechanistic investigation of an amorphous pharmaceutical and its solid dispersions, part I: a comparative analysis by thermally stimulated depolarization current and differential scanning calorimetry.

PURPOSE: To explore using thermally stimulated depolarization current (TSDC), in comparison to differential scanning calorimetry (DSC), for the characterization of molecular mobility of an amorphous pharmaceutical new chemical entity (LAB687), an amorphous polymer (PVPK-30), and their combination as solid dispersions at different % drug loadings. METHODS: Amorphous drug was prepared by quenching from the melt. Solid dispersions containing 10-60% of drug in polymer were prepared by solvent evaporation method. Glass transition temperatures (Tg) were determined by DSC and TSDC. RESULTS: In comparison to a single T. obtained from DSC for the drug substance, TSDC shows two overlapping relaxations. Both peaks correspond to a-relaxations that are associated with the glass transition, with the second peak corresponding to the rigid fraction that is difficult to be detected by DSC because it is associated with only small changes in heat capacity. Two overlapping relaxations were also observed for the polymer vs. one Tg by DSC. The lower temperature relaxation is believed to be a beta-relaxation, whereas the higher temperature transition corresponds to an alpha-relaxation. For the solid dispersions, one single peak was obtained for each of the 20% and 30% dispersions in excellent agreement with the DSC results. However, at the 40% drug load, a small shoulder was observed by TSDC at the low temperature of the main peak. This shoulder becomes more pronounced and overlaps with the main peak as the drug load increases to 50% and 60%. Agreement between the Tg values calculated by the Gordon-Taylor equation and the DSC and TSDC experimental data, especially for the 20% and 30% drug loading, indicate ideal miscibility. At higher drug loads, only by TSDC was it possible to detect the saturation level of the drug in the polymer. CONCLUSIONS: TSDC proved to be very sensitive in detecting small reorientational motions in solids and in separating overlapping events with only slight differences in molecular motion exhibited as broad events in DSC. This allowed for detection of the rigid fraction of the amorphous drug, the sub-glass transition beta- relaxation in the polymer, and the limit of miscibility between the drug and the polymer in the solid dispersions.

A mechanistic investigation of an amorphous pharmaceutical and its solid dispersions, part II: molecular mobility and activation thermodynamic parameters.

PURPOSE: The ability of TSDC to characterize further amorphous materials beyond that possible with DSC was presented in part I (16) of this work. The purpose of part II presented here is to detect and quantitatively characterize time-scales of molecular motions (relaxation times) in amorphous solids at and below the glass transition temperature, to determine distributions of relaxation times associated with different modes of molecular mobility and their temperature dependence, and to determine experimentally the impact upon these parameters of combining the drug with excipients (i.e., solid dispersions at different drug to polymer ratios). The knowledge gleaned may be applied toward a more realistic correlation with physical stability of an amorphous drug within a formulation during storage. METHODS: Preparation of amorphous drug and its solid dispersions with PVPK-30 was described in part I (16). Molecular mobility and dynamics of glass transition for these systems were studied using TSDC in the thermal windowing mode. RESULTS: Relaxation maps and thermodynamic activation parameters show the effect of formulating the drug in a solid dispersion on converting the system (drug alone) from one with a wide distribution of motional processes extending over a wide temperature range at and below Tg to one that is homogeneous with very few modes of motion (20% dispersion) that becomes increasingly less homogeneous as the drug load increases (40% dispersion). This is confirmed by the high activation enthalpy (due to extensive intra- and intermolecular interactions) as well as high activation entropy (due to higher extent of freedom) for the drug alone vs. a close to an ideal system (lower enthalpy), with less extent of freedom (low entropy) especially for the 20% dispersion. The polymer PVPK-30 exhibited two distinct modes of motion, one with higher values of activation enthalpies and entropy corresponding to alpha-relaxations, the other with lower values corresponding to beta-relaxations characterized by local noncooperative motional processes. CONCLUSIONS: Using thermal windowing, a distribution of temperature-dependent relaxation times encountered in real systems was obtained as opposed to a single average value routinely acquired by other techniques. Relevant kinetic parameters were obtained and used in mechanistically delineating the effects on molecular mobility of temperature and incorporating the drug in a polymer. This allows for appropriate choices to be made regarding drug loading, storage temperature, and type of polymer that would realistically correlate to physical stability.