From bench to humans: formulation development of a poorly water soluble drug to mitigate food effect.

This study presents a formulation approach that was shown to mitigate the dramatic food effect observed for a BCS Class II drug. In vitro (dissolution), in vivo (dog), and in silico (GastroPlus®) models were developed to understand the food effect and design strategies to mitigate it. The results showed that such models can be used successfully to mimic the clinically observed food effect. GastroPlus® modeling showed that food effect was primarily due to the extensive solubilization of the drug into the dietary lipid content of the meal. Several formulations were screened for dissolution rate using the biorelevant dissolution tests. Surfactant type and binder amount were found to play a significant role in the dissolution rate of the tablet prototypes that were manufactured using a high-shear wet granulation process. The performance of the lead prototypes (exhibiting best in vitro dissolution performance) was tested in dogs and human subjects. A new formulation approach, where vitamin E TPGS was included in the tablet formulation, was found to mitigate the food effect in humans.

Role of drug substance material properties in the processibility and performance of a wet granulated product.

The purpose of this study was to establish a relationship between the material properties of an active pharmaceutical ingredient (API) and its behavior during high-shear wet granulation. Using several actives and excipients as material probes, the influence of aqueous solubility, wettability, water holding capacity, mean and width of the particle size distribution, and surface area was examined. The effect of these variables on the processibility and performance of the granulations was evaluated by monitoring such responses as granule growth, compactability and flow changes upon wet granulation. The prominent findings from this study include: (a) controlled growth is highest in readily wettable APIs with low surface area, (b) uncontrolled growth is high in APIs of high solubility and low water holding capacity, (c) polydisperse granulations are produced from APIs of high contact angle and surface area, (d) improvement in compactability is high in APIs with large surface area and broader size distributions and (e) flow enhancement as a result of wet granulation is highest in APIs of large size distributions. These results are physically interpreted in this manuscript based on the prevailing wet granulation theories. Findings from this study are useful in mapping a new material to predict its performance in a high-shear wet granulation process.

Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer-surfactant combinations using solubility parameters and testing the processability.

Formation of solid dispersions as a means to enhance the dissolution rate of poorly soluble Active pharmaceutical ingredients (APIs) typically employs hydrophilic polymer systems and surfactants. While the utility of the surfactant systems in solubilization is well known, the secondary effects of the same on processing and subsequent physical stability of the solid dispersions needs to be studied further. Physical blends of the poorly soluble API and hydrophilic polymers such as PVP-K30, Plasdone-S630, HPMC-E5, HPMCAS, and Eudragit L100 with mass ratio 1:1 were prepared. The surfactants tested in this study included Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and SLS. Thermal analysis of the API-polymer-surfactant blends suggested that the surfactants caused solvation/plasticization, manifesting in reduction of (i) the melting (T(m)) of API (ii) T(g) of the polymers and (iii) the combined T(g) of the solid dispersion formed from quench cooling. Explanation of these effects of surfactants is attempted based on their physical state (at the temperature of interest), HLB values and similarity of their solubility parameter values with respect to drug-polymer systems. Furthermore, extruded matrices containing different API-polymer (PVP-K30, Plasdone-S630, and HPMC-E5) mixtures prepared with and without surfactants, were produced by feeding the powder blend through a hot-melt extruder. The melt viscosity of the polymer blends was assessed by torque rheometry using a Haake Rheomix. The physicochemical properties of the extruded API-polymer-surfactant were characterized by differential scanning calorimetry, X-ray diffraction, Raman spectroscopy, and polarized microscopy. The results demonstrated that the glass transition temperature of the carrier polymers decreased as direct result of the surfactants in the extrudate, due to an increase in the chain mobility of polymers. A decrease in the melt viscosity was seen due to a plasticization of the polymer. The drug release profiles of the extruded solid dispersions containing intra granular surfactants were found to fit the dispersions with extra granularly added surfactants.

Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: stability testing of selected solid dispersions.

PURPOSE: The purpose of the study is to evaluate the effect of surfactant-plasticizers on the physical stability of amorphous drug in polymer matrices formed by hot melt extrusion. METHOD: Solid dispersions of a poorly soluble drug were prepared using PVP-K30, Plasdone-S630, and HPMC-E5 as the polymeric carriers and surfactants as plasticizers. The solid dispersions were produced by hot melt extrusion at temperatures 10 degrees C above and below the glass transition temperature (Tg) of the carrier polymers using a 16 mm-Haake Extruder. The surfactants tested in this study included Tween-80 and Docusate Sodium. The particle size of the extrudate was reduced to have mean of 100-200 micron. The physical stability of the solid dispersions produced was monitored at 30 degrees C/60% for six-months and at 60 degrees C/85% for two-months in open HDPE bottles. Modulated differential scanning calorimetry, polarized light microscopy, powder X-ray diffraction and dissolution testing was performed to assess the physical stability of solid dispersions upon stress testing. RESULTS: The dispersions containing HPMC-E5 were observed especially to be susceptible to physical instability under an accelerated stress conditions (60 degrees C/85%RH) of the solid dispersion. About 6% conversion of amorphous drug to crystalline form was observed. Consequently, the system exhibits similar degree of re-crystallization upon addition of the surfactant. However, under 30 degrees C/60%RH condition, the otherwise amorphous Drug-HPMC-E5 system has been destabilized by the addition of the surfactant. This effect is much more reduced in the extruded solid dispersions where polymeric carriers such as Plasdone S-603 and PVP-K30 (in addition to surfactants) are present. Furthermore, the drug release from the solid dispersions was unaffected at the stress conditions reported above. CONCLUSIONS: Possible reasons for the enhanced stability of the dispersions are due to the surfactants ability to lower the viscosity of the melt, increase the API solubility and homogeneity in the carrier polymer. In contrast, while it is possible for the surfactants to destabilize the system by lowering the Tg and increasing the water uptake, the study confirms that this effect is minimal. By and large, the surfactants appear to be promising plasticizers to produce solid dispersions by hot melt extrusion, in so doing improving dissolution rate without compromising the physical stability of the systems.

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.

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.