Factors affecting incorporation of drug into solid solution with HPMCP during solvent change co-precipitation

TY - JOUR

T1 - Factors affecting incorporation of drug into solid solution with HPMCP during solvent change co-precipitation

AU - Sertsou, Gabriel

AU - Butler, James

AU - Scott, Andy

AU - Hempenstall, John

AU - Rades, Thomas

PY - 2002/10/1

Y1 - 2002/10/1

N2 - Drug-hydroxypropyl methylcellulose phthalate (HPMCP) mixtures were completely dissolved in acetone, and the resulting solution was added drop-wise into HCl(aq). Resulting co-precipitates were filtered, and then dried under vacuum at 45 degrees C, -800 mbar for 24 h. Modulated differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction and HPLC were used to detect and quantify different phases present in co-precipitates. A 1/8 factorial study followed by a circumscribed central composite (CCC) study of significant factors, were used to detect and quantify respectively, the effects that processing factors had on the percentage of drug present in co-precipitates which was incorporated into solid solution (the response). Robustness of the model obtained from the CCC study was tested. Statistically significant factors were found to be the percentage of drug added into solvent, stirrer speed, and antisolvent pH. The statistically significant mathematical model obtained from the CCC study predicted that the dominant factor influencing the response is the percentage of drug added into solvent. The effect of stirrer speed on the response includes a local maximum at stirrer speed approximately 700 rpm. Both stirrer speed and antisolvent pH showed interactions with the percentage of drug added into solvent. The model obtained from this study indicated the possibility of two opposing phenomena influencing the response: crystallization inhibition by HPMCP, and solvent-antisolvent plasticization. Testing of this model using eight experimentally determined points showed reasonable robustness, with six out of eight points lying inside 95% prediction intervals.

AB - Drug-hydroxypropyl methylcellulose phthalate (HPMCP) mixtures were completely dissolved in acetone, and the resulting solution was added drop-wise into HCl(aq). Resulting co-precipitates were filtered, and then dried under vacuum at 45 degrees C, -800 mbar for 24 h. Modulated differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction and HPLC were used to detect and quantify different phases present in co-precipitates. A 1/8 factorial study followed by a circumscribed central composite (CCC) study of significant factors, were used to detect and quantify respectively, the effects that processing factors had on the percentage of drug present in co-precipitates which was incorporated into solid solution (the response). Robustness of the model obtained from the CCC study was tested. Statistically significant factors were found to be the percentage of drug added into solvent, stirrer speed, and antisolvent pH. The statistically significant mathematical model obtained from the CCC study predicted that the dominant factor influencing the response is the percentage of drug added into solvent. The effect of stirrer speed on the response includes a local maximum at stirrer speed approximately 700 rpm. Both stirrer speed and antisolvent pH showed interactions with the percentage of drug added into solvent. The model obtained from this study indicated the possibility of two opposing phenomena influencing the response: crystallization inhibition by HPMCP, and solvent-antisolvent plasticization. Testing of this model using eight experimentally determined points showed reasonable robustness, with six out of eight points lying inside 95% prediction intervals.

KW - Acetone

KW - Calorimetry, Differential Scanning

KW - Chromatography, High Pressure Liquid

KW - Drug Compounding

KW - Factor Analysis, Statistical

KW - Fractional Precipitation

KW - Hydrocarbons, Aromatic

KW - Methylcellulose

KW - Models, Chemical

KW - Nitrogen

KW - Pyrazoles

KW - Pyridazines

KW - Solubility

KW - Solvents

KW - Thermogravimetry

KW - X-Ray Diffraction

M3 - Journal article

C2 - 12270247

SN - 0378-5173

VL - 245

SP - 99

EP - 108

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

IS - 1-2

ER -