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Narang A.S.,Drug Product Science and Technology | Badawy S.,Drug Product Science and Technology | Ye Q.,Analytical and Bioanalytical Development | Patel D.,Drug Product Science and Technology | And 11 more authors.
Pharmaceutical Research | Year: 2015

Purpose: Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated.Methods: Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables.Results: Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data.Conclusions: Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation. © 2015 Springer Science+Business Media New York


Derdour L.,Drug Product Science and Technology | Skliar D.,Bristol Myers Squibb
Crystal Growth and Design | Year: 2012

A mechanistic model for supersaturation and crystal growth during batch crystallization of organic solids from solutions containing multiple conformers is presented. The model is based on the approach of the right conformer (RC) which assumes that only one conformer participates in the surface integration step. The model is concerned with systems characterized by slow crystal growth and low supersaturation, a behavior favored when the RC is the minority species in solution. Crystal growth is assumed to occur via a step advance mechanism with a variable step advance velocity (VSAV). Model derivation indicated that when the approach of the RC applies, crystal growth is inversely proportional to crystal size. Lastly, model simulations predicted an exponential increase of maximum relative supersaturation with linear antisolvent addition rate. The simulation also allowed estimation of maximum addition rate below which secondary nucleation is minimized. © 2012 American Chemical Society.


Hsieh D.S.,Drug Product Science and Technology | Roberts D.,Drug Product Science and Technology | Rosner T.,Bristol Myers Squibb | Rosenbaum T.,Drug Product Science and Technology | And 2 more authors.
Crystal Growth and Design | Year: 2016

A novel pure component approach using HyperDSC for the relative stability determination was reported in 2012 (Hsieh et al. Cryst. Growth Des. 2012, 12, 5481). The accuracy of this approach depends upon the accurate physical properties of the amorphous and crystalline phases, including heat capacity and heat of fusion. However, it has been encountered that the heat of fusion for some pharmaceutical compounds cannot be accurately determined due to thermal decomposition or recrystallization upon melting even at very high heating rate. Hence, we report here two new methods for accurate heat of fusion determination using a combination of solid-state and solution calorimetry, determining the heat of solution at temperatures much lower than the melting point, thus avoiding decomposition or recrystallization. The theoretical derivation and experimental procedure for these two methods are reported in this study. The theoretical derivation of thermodynamic equations relates the solid-state and solution approaches. The experimental approach focuses on the use of solution calorimetry to measure the enthalpy difference between the amorphous and crystalline phases or between the polymorphs. A system composed of five polymorphs has been used to verify the methodology and its extension. The heat of fusion for the five polymorphs determined from the new methods are in good agreement with those from HyperDSC. A phase diagram using the heat of fusion determined from this study can be generated to rank the relative stability among the five polymorphs as a function of temperature. © 2015 American Chemical Society.


PubMed | Drug Product Science and Technology
Type: Journal Article | Journal: Pharmaceutical development and technology | Year: 2013

Development of 0.1, 0.5, and 1.0mg entecavir tablet formulations for the treatment of hepatitis B virus was challenging for content uniformity. Entecavir with pKa of 2.8 and 9.8 does not have sufficient solubility in acidic or alkaline medium or in common pharmaceutical solvents such as ethanol to dissolve the drug in granulating fluid to prepare the homogeneous granulation. Povidone (PVP), a commonly used binder, was found to increase entecavir solubility depending on the PVP concentration and temperature of the solution. At 15% w/w PVP concentration, entecavir solubility increased from 2mg/mL to about 8mg/mL at room temperature. When the PVP solution was heated to 50C or 70C, the solubility was increased to about 23 or 33mg/mL, respectively. Based on Raman spectra of entecavir in PVP solution, the increase in entecavir solubility in the presence of PVP may not be due to any molecular interactions between them. Solubilization of entecavir in PVP and eventual granulation did not change the polymorphic form of the drug based on the powder X-ray and differential scanning calorimetric (DSC), and thermo-gravimetric analysis (TGA) of neat entecavir re-crystallized from the PVP solution. The enhancement in the solubility of entecavir by PVP was sufficient to keep the amount of solution, which was used for granulation, to be about 20% w/w of the batch size like the traditional aqueous granulation. The granulation manufactured using this approach provided better tablet content uniformity than one using micronized entecavir.


Pandey P.,Drug Product Science and Technology | Ji J.,Drug Product Science and Technology | Subramanian G.,Drug Product Science and Technology | Gour S.,Drug Product Science and Technology | Bindra D.S.,Drug Product Science and Technology
Drug Development and Industrial Pharmacy | Year: 2014

Objective: The objective of the current study was to establish the use of PyroButton data-logging device to monitor and quantify the thermodynamic environment (temperature and humidity) of a pan coating process. Material and methods: PyroButtons were placed (fixed) at various locations in a pan coater, including exhaust plenum, spray-gun bar, baffles and were also allowed to freely move with the tablet-bed. A full factorial design of experiments (DOE) study on three process parameters, exhaust temperature, pan speed and spray rate was conducted on a 24 inch pan coater, using a coating system and a core tablet combination expected to have a narrow process operating space. Results: It was shown that the PyroButtons can provide a detailed and useful signature of the coating process. PyroButton data showed that the tablet-bed temperature was always lower than exhaust temperature and that the difference was a function of the operating conditions such as spray rate. Similarly, the tablet-bed humidity was found to always be higher than exhaust humidity. Some of the DOE batches showed coating defects (logo-bridging). It was shown that the relative humidity (RH), as measured by the freely-moving PyroButtons in the tablet-bed, correlated well with the logo-bridging events. A critical RH value (30%) was established, above which logo-bridging was observed for the selected formulation. Conclusions: This study showed that PyroButtons can provide very meaningful micro-environmental data that can be correlated to coating defects, and can aid in establishing a process design space for a given coating and tablet formulation. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


PubMed | Drug Product Science and Technology
Type: Journal Article | Journal: Pharmaceutical research | Year: 2015

Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated.Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables.Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data.Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.

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