Aditya Mohan Kaushal

Lubrication Potential of Magnesium Stearate Studied on Instrumented Rotary Tablet Press

The aim of this study was to investigate the lubrication potential of 2 grades of magnesium stearate (MS) blended with a mix of dicalcium phosphate dihydrate and microcrystalline cellulose. Force-displacement, force-time, and ejection profiles were generated using an instrumented rotary tablet press, and the effect of MS mixing time (10, 20, and 30 minutes) and tableting speed (10.7, 13.8, and 17.5 rpm) was investigated. The packing index (PI), frictional index (FI), and packing energy (PE) derived from the force-displacement profiles showed that MS sample I performed better than sample II. At higher lubricant mixing times, the values of PI were observed to increase, and values of FI and PE were observed to decrease for both MS samples. Lower values of area under the curve (AUC) calculated from force-time compression profiles also showed sample I to be superior to sample II in lubrication potential. For both the samples, the values of AUC were observed to decrease with higher lubricant mixing times. Tapping volumetry that simulates the initial particle rear-rangement gave values of parameter a and Cmax that were higher for sample I than sample II and also increased with lubricant mixing time. The superior lubrication potential of sample I was also established by the lower values of peak ejection force encountered in the ejection profile. Lower ejection forces were also found to result from higher tableting speeds and longer lubricant mixing times. The difference in lubrication efficacy of the 2 samples could be attributed to differences in their solid-state properties, such as particle size, specific surface area, and d-spacing.

Thermodynamic behavior of glassy state of structurally related compounds.

Thermodynamic properties of amorphous pharmaceutical forms are responsible for enhanced solubility as well as poor physical stability. The present study was designed to investigate the differences in thermodynamic parameters arising out of disparate molecular structures and associations for four structurally related pharmaceutical compounds--celecoxib, valdecoxib, rofecoxib, and etoricoxib. Conventional and modulated temperature differential scanning calorimetry were employed to study glass forming ability and thermodynamic behavior of the glassy state of model compounds. Glass transition temperature of four glassy compounds was in a close range of 327.6-331.8 K, however, other thermodynamic parameters varied considerably. Kauzmann temperature, strength parameter and fragility parameter showed rofecoxib glass to be most fragile of the four compounds. Glass forming ability of the compounds fared similar in the critical cooling rate experiments, suggesting that different factors were determining the glass forming ability and subsequent behavior of the compounds in glassy state. A comprehensive understanding of such thermodynamic facets of amorphous form would help in rationalizing the approaches towards development of stable glassy pharmaceuticals.

Impact of Solid-State Properties on Lubrication Efficacy of Magnesium Stearate

The advent of high-speed tableting and slug capsule-filling machines has ushered in an increasingly important role for the lubricants to enact during manufacturing of dosage forms. Although lubricants help in processing, they can also adversely affect the flow properties and dissolution profile of the drug. It is thus critical to maintain a balance between these two behaviors, by understanding the underlying mechanisms and using their optimum concentration in the formulation. The source and manufacturing process inculcate different solid-state properties to magnesium stearate, the most commonly used lubricant, leading to variations in its lubrication efficacy. However, there has been no complete study relating the lubrication efficacy of magnesium stearate to various levels of solid state. Hence, this study was aimed at comprehensively scrutinizing the role of molecular, particle, and bulk level properties of solid state on the lubrication efficacy of magnesium stearate. A method based on net work done during compression using texture analyzer, was developed and validated to analyze its performance. Particle and bulk-level properties were studied using microscopy, particle size analysis, and particle surface area determination, and molecular level was characterized using thermal, spectroscopic, and crystallographic methods. Interplay of solid-state characteristics such as particle size, degree of agglomeration, and crystal habit were found to markedly influence the lubrication potential of magnesium stearate.

Compaction behavior of roller compacted ibuprofen

The effect of roller compaction pressure on the bulk compaction of roller compacted ibuprofen was investigated using instrumented rotary tablet press. Three different roller pressures were utilized to prepare granules and Heckel analysis, Walker analysis, compressibility, and tabletability were performed to derive densification, deformation, course of volume reduction and bonding phenomenon of different pressure roller compacted granules. Nominal single granule fracture strength was obtained by micro tensile testing. Heckel analysis indicated that granules prepared using lower pressure during roller compaction showed lower yield strength. The reduction in tabletability was observed for higher pressure roller compacted granules. The reduction in tabletability supports the results of granule size enlargement theory. Apart from the granule size enlargement theory, the available fines and relative fragmentation during compaction is responsible for higher bonding strength and provide larger areas for true particle contact at constant porosity for lower pressure roller compacted granules. Overall bulk compaction parameters indicated that granules prepared by lower roller compaction pressure were advantageous in terms of tabletability and densification. Overall results suggested that densification during roller compaction affects the particle level properties of specific surface area, nominal fracture strength, and compaction behavior.

Mechanistic investigation on pressure dependency of Heckel parameter.

This work proposed to study the influence of varying compaction pressure on the plastic energy, elasticity (Youngs modulus), particle yield strength, strain hardening, and applied pressures on derived Heckel parameter using material with different densification and deformation mechanisms: ibuprofen (IBN), paracetamol (PCM) (elastic behavior), methyl cellulose (Me-Cel), microcrystalline cellulose (MCC), sodium chloride (NaCl) (plastic behavior), and dicalcium phosphate (DCP) (brittle fracture). Force-displacement data were captured during in-die compaction for all materials having different deformation behavior. The apparent mean yield pressure (Py), plastic energy, Youngs moduli, strain hardening parameter and rate of increase in Py were calculated from force-displacement compaction profiles obtained across a pressure range of 65-260 MPa. Materials under confined compression loading showed pressure dependent biphasic behavior in Py upon increasing pressure from 65 MPa to 260 MPa. IBN and PCM showed pressure dependency due to simultaneous elasticity and strain hardening upon increasing applied pressure. Me-Cel, MCC, and NaCl showed lower pressure dependency while DCP showed higher change in Py upon increasing pressure as a result of higher yield strength of DCP particles. Apparent mean yield pressure from Heckel analysis was significantly affected by the applied pressure, viscoelastic behavior, particle yield strength, and strain hardening. The simultaneously occurring events of elastic deformation and strain hardening give a false increase in Py at higher applied pressures.

Effect of counterions on the properties of amorphous atorvastatin salts

Amorphous systems have gained importance as a tool for addressing delivery challenges of poorly water soluble drugs. A careful assessment of thermodynamic and kinetic behavior of amorphous form is necessary for successful use of amorphous form in drug delivery. The present study was undertaken to evaluate effect of monovalent sodium (Na(+); ATV Na), and bivalent calcium (Ca(2+); ATV Ca) and magnesium (Mg(2+); ATV Mg) counterions on properties of amorphous salts of atorvastatin (ATV) model drug. Amorphous form was generated from crystalline salts of ATV by spray drying, and characterized for glass transition temperature (T(g)), fragility and devitrification tendency. In addition, chemical stability of the amorphous salt forms was evaluated. Fragility was studied by calculating activation enthalpy for structural relaxation at T(g), from heating rate dependency of T(g). Density functional theory and relative pK(a)s of counterions were evaluated to substantiate trend in glass transition temperature. T(g) of salts followed order: ATV Ca>ATV Mg>ATV Na. All salts were fragile to moderately fragile, with D value ranging between 9 and 16. Ease of devitrification followed the order: ATV Na∼ATV Mg≫ATV Ca, using isothermal crystallization and reduced crystallization temperature method. Chemical stability at 80°C showed higher degradation of amorphous ATV Ca (∼5%), while ATV Na and ATV Mg showed degradation of 1-2%. Overall, ATV Ca was better in terms of glass forming ability, higher T(g) and physical stability. The study has importance in selection of a suitable amorphous form, during early drug development phase.

Enthalpy relaxation studies of two structurally related amorphous drugs and their binary dispersions

Objective: The purpose of the current study was to evaluate the enthalpy relaxation behavior of valdecoxib (VLB) and etoricoxib (ETB) and their binary dispersions to derive relaxation constants and to understand their molecular mobilities. Methods: Solid dispersions of VLB and ETB were prepared with 1%, 2%, 5%, 10%, 15%, and 20% (w/w) concentrations of polyvinylpyrrolidone (PVP) in situ using differential scanning calorimetry (DSC). Enthalpy relaxation studies were carried out with isothermal storage periods of 1, 2, 4, 6, 16, and 24 hours at 40°C and 0% relative humidity (RH). Results: PVP increased the glass transition temperature (Tg) and decreased the enthalpy relaxation. Significant differences between two drugs were observed with respect to their relaxation behavior which may be due to differences in intermolecular interactions as predicted by Couchman–Karasz equation and molecular mobility. Kohlrausch–Williams–Watts equation was found to be inadequate in describing complex molecular relaxations in binary dispersions. The enthalpy relaxation behavior of VLB and ETB was found to be significantly different. PVP stabilized VLB significantly; however, its effect on ETB was negligible. The extent of enthalpy relaxation was found to correlate with hydrogen bonding tendency of the drug molecules. Conclusion: The outcome can help in rational designing of amorphous systems with optimal performance.

Erratum to: The Stabilizing Effect of Moisture on the Solid-State Degradation of Gabapentin

Erratum to: AAPS PharmSciTech DOI 10.1208/s12249-011-9652-8 ACKNOWLEDGEMENTS We are grateful to the National Institute for Pharmaceutical Technology and Education (NIPTE) and the U.S. Food and Drug Administration (FDA) for providing funds for this research. This study was funded by the FDA-sponsored contract “Development of Quality by Design (QbD) Guidance Elements on Design Specifications across Scales with Stability Considerations” (contract number HHSF223200819929C).