Kailas S. Khomane

Molecular understanding of the compaction behavior of indomethacin polymorphs.

Polymorphs enable us to gain molecular insights into the compaction behavior of pharmaceutical powders. Two polymorphs (α and γ) of indomethacin (IMC) were investigated for in-die and out-of-die compaction behavior using compressibility, tabletability and compactibility (CTC) profile, stress-strain relationship, and Heckel, Kawakita and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. CTC analysis revealed that the γ-form has increased compressibility while the α-form showed greater compactibility. The α-form also showed increased tabletability over the γ-form at all the compaction pressures. Lower values of Py (Heckel parameter) and 1/b (Kawakita parameter) indicated increased deformation behavior of γ-form. Stress-strain analysis also supports the increased compressibility of γ-form. In addition, Walker analysis showed higher compressibility coefficient (W) for α-form, consistent with its greater tabletability. Thus, tabletability of IMC polymorphs was governed by the compactibility of the material. Detailed examination of crystallographic data revealed that the presence of a slip plane system in the γ-form offered it increased compressibility and deformation behavior. However, the α-form showed greater compactibility by virtue of closer molecular packing (higher true density). Hence, although direct correlation between tabletability and the presence of slip planes in the crystals has been reported, prediction solely based on this crystallographic feature must be avoided. The present work reiterates the influence of the crystal packing on the tabletability of the pharmaceutical polymorphs.

Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs.

Being a density violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of molecular packing (true density) and thermodynamic properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examinations of the molecular packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of molecules in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true density and lower heat of fusion showed higher bonding strength. Hence, true density and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders.

Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs

Polymorphism plays a critical role during pharmaceutical development, as it helps in the selection of optimal solid form. In present study, mechanical properties of ranitidine hydrochloride polymorphs were studied using instrumented tablet press, to understand the effect of crystal packing on the compaction behaviour. Out-of-die compressibility plot and Heckel analysis confirmed greater plastic deformation of form II over form I. Detailed crystallographic examination revealed that form I has several weak C–H⋯O interactions across the ‘proposed slip plane’ parallel to (−2 0 2) that prevent slip under compaction pressure. On the other hand, crystal structure of form II was relatively more open and multiple slip were possible under compaction pressure. These crystallographic features offered increased compressibility and deformability to form II. In absence of an active slip plane system, closed crystal structure of form I resists deformation under compaction pressure and hence showed poor compressibility and higher mean yield pressure. However, form I showed greater tabletability at a given compaction pressure, by virtue of its greater bonding strength.

Effect of Particle Size on In-die and Out-of-die Compaction Behavior of Ranitidine Hydrochloride Polymorphs

The present study investigates the effect of particle size on compaction behavior of forms I and II of ranitidine hydrochloride. Compaction studies were performed using three particle size ranges [450–600 (A), 300–400 (B), and 150–180 (C) μm] of both the forms, using a fully instrumented rotary tableting machine. Compaction data were analyzed for out-of-die compressibility, tabletability, and compactibility profiles and in-die Heckel and Kawakita analysis. Tabletability of the studied size fractions followed the order; IB > IA > > IIC > IIB > IIA at all the compaction pressures. In both the polymorphs, decrease in particle size improved the tabletability. Form I showed greater tabletability over form II at a given compaction pressure and sized fraction. Compressibility plot and Heckel and Kawakita analysis revealed greater compressibility and deformation behavior of form II over form I at a given compaction pressure and sized fraction. Decrease in particle size increased the compressibility and plastic deformation of both the forms. For a given polymorph, improved tabletability of smaller sized particles was attributed to their increased compressibility. However, IA and IB, despite poor compressibility and deformation, showed increased tabletability over IIA, IIB, and IIC by virtue of their greater compactibility. Microtensile testing also revealed higher nominal fracture strength of form I particles over form II, thus, supporting greater compactibility of form I. Taken as a whole, though particle size exhibited a trend on tabletability of individual forms, better compactibility of form I over form II has an overwhelming impact on tabletability.

Implication of microstructure on the mechanical behaviour of an aspirin–paracetamol eutectic mixture

The present work investigates the mechanical behaviour of an aspirin–paracetamol (ASP–PCM) eutectic mixture (EM). A EM of ASP–PCM was prepared using a solvent evaporation method. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) confirmed the eutectic formation with a composition of 53:47% w/w (ASP:PCM). The compaction behaviour of the EM and a physical mixture (PM) of ASP and PCM was compared using a fully instrumented rotary tablet press equipped with a Portable Press Analyzer™ (PPA). The obtained data were compared using compressibility, tabletability and compactibility profiles and Heckel analysis. The EM exhibited higher compressibility, tabletability and plastic deformation compared to the PM. Heckel analysis showed that the mean yield pressure, Py, was lower for the EM (46.9 MPa) than the PM (222.8 MPa), thus confirming the better plastic deformation of the EM. The better deformation behaviour of the EM was attributed to its layered microstructure. The sliding of adjacent layers over each other under an applied compaction pressure offered higher plastic deformation and thus provided a greater interparticulate bonding area in the EM compared to the PM. However, there was no significant difference in the compactibility profiles indicating a similar interparticulate bonding strength of the two powders. Thus, the EM showed better tabletability compared to the PM by virtue of its greater compressibility and plastic deformation.

Mechanistic Insights into PEPT1-Mediated Transport of a Novel Antiepileptic, NP-647

The present study, in general, is aimed to uncover the properties of the transport mechanism or mechanisms responsible for the uptake of NP-647 into Caco-2 cells and, in particular, to understand whether it is a substrate for the intestinal oligopeptide transporter, PEPT1 (SLC15A1). NP-647 showed a carrier-mediated, saturable transport with Michaelis-Menten parameters K(m) = 1.2 mM and V(max) = 2.2 μM/min. The effect of pH, sodium ion (Na(+)), glycylsarcosine and amoxicillin (substrates of PEPT1), and sodium azide (Na(+)/K(+)-ATPase inhibitor) on the flux rate of NP-647 was determined. Molecular docking and molecular dynamics simulation studies were carried out to investigate molecular interactions of NP-647 with transporter using homology model of human PEPT1. The permeability coefficient (P(appCaco-2)) of NP-647 (32.5 × 10(-6) cm/s) was found to be four times higher than that of TRH. Results indicate that NP-647 is transported into Caco-2 cells by means of a carrier-mediated, proton-dependent mechanism that is inhibited by Gly-Sar and amoxicillin. In turn, NP-647 also inhibits the uptake of Gly-Sar into Caco-2 cells and, together, this evidence suggests that PEPT1 is involved in the process. Docking and molecular dynamics simulation studies indicate high affinity of NP-647 toward PEPT1 binding site as compared to TRH. High permeability of NP-647 over TRH is attributed to its increased hydrophobicity which increases its affinity toward PEPT1 by interacting with the hydrophobic pocket of the transporter through hydrophobic forces.

Weak Hydrogen Bonding Interactions Influence Slip System Activity and Compaction Behavior of Pharmaceutical Powders

Markedly different mechanical behavior of powders of polymorphs, cocrystals, hydrate/anhydrate pairs, or structurally similar molecules has been attributed to the presence of active slip planes system in their crystal structures. Presence of slip planes in the crystal lattice allows easier slip under the applied compaction pressure. This allows greater plastic deformation of the powder and results into increased interparticulate bonding area and greater tensile strength of the compacts. Thus, based on this crystallographic feature, tableting performance of the active pharmaceutical ingredients can be predicted. Recently, we encountered a case where larger numbers of CH···O type interactions across the proposed slip planes hinder the slip and thus resist plastic deformation of the powder under the applied compaction pressure. Hence, attention must be given to these types of interactions while identifying slip planes by visualization method. Generally, slip planes are visualized as flat layers often strengthened by a two-dimensional hydrogen-bonding network within the layers or planes. No hydrogen bonding should exist between these layers to consider them as slip planes. Moreover, one should also check the presence of CH···O type interactions across these planes. Mercury software provides an option for visualization of these weak hydrogen bonding interactions. Hence, caution must be exercised while selecting appropriate solid form based on this crystallographic feature.

Impact of differential surface molecular environment on the interparticulate bonding strength of celecoxib crystal habits.

The present work investigates the impact of milling on differential compactibility behavior of celecoxib (CEL) crystal habits. Plate shaped (CEL-P) crystals showed better compactibility over acicular (CEL-A) crystals. Milling improved the compactibility of both the forms. However, despite similar particle shape, size, and surface area, milled fractions of the two habits showed significantly different interparticulate bonding strength. The greater bonding strength of milled CEL-P (MCEL-P) over milled CEL-A (MCEL-A) was attributed to the differential cleavage behavior of the two habits that conferred the different surface molecular environment to the milled powders. The preferred cleavage of CEL-P across {020} plane exposed the -CF3 group and the methyl phenyl ring on the surface of MCEL-P. On the other hand, CEL-A preferentially fractured along their shortest axis that increased the exposure of {100} plane on the surface of MCEL-A, which exposed the -CF3 group and the pyrazole ring. Surface free energy quantified by determining advancing contact angle revealed greater dispersive component of MCEL-P over MCEL-A. This is consistent with the differential cleavage behavior of CEL-P and CEL-A. This confirmed the role of dispersive component of surface free energy in governing interparticulate bonding strength of CEL. The study supports the postulate that tablet tensile strength is governed by the dispersive intermolecular interactions formed over the interparticulate bonding area.

Investigating permeability related hurdles in oral delivery of 11-keto-β-boswellic acid

11-Keto-β-boswellic acid (KBA) is an important and potent boswellic acids responsible for anti-inflammatory action of Boswellia extract. However, its pharmaceutical development has been severely limited by its poor oral bioavailability. The present work aims to investigate the permeability related hurdles in oral delivery of KBA. Gastrointestinal stability, gastrointestinal metabolism, adsorption-desorption kinetics and Caco-2 permeability studies have been carried out. KBA was found poorly permeable with Papp value of 2.85 ± 0.14 × 10(-6)cm/s. Higher absorptive transport indicated role of carrier mediated transport. Moreover, KBA transport across monolayer showed saturation kinetics at higher concentrations. KBA exposed to 1α,25-(OH)2 vitamin D3 treated cell monolayer showed the lowest Papp value of 2.01×10(-6) ± 0.02 × 10(-6)cm/s indicating role of CYP3A4 mediated metabolism during KBA transport. Metabolic stability experiments in jejunum S9 fractions further confirmed this. KBA was found unstable in simulated gastrointestinal fluids and also got accumulated in the enterocytes. Sorption and desorption kinetic studies using Caco-2 cells further confirmed accumulation of KBA inside the enterocytes. KBA also showed pH dependent permeability with higher flux at gradient pH condition of pH 6.5 at apical and 7.4 at basolateral. Taken as whole, the major permeability related hurdles that hampered oral bioavailability of KBA included its gastrointestinal instability, CYP3A4 mediated intestinal metabolism, accumulation within the enterocytes and saturable kinetics. The present investigation may help in designing novel drug delivery system for KBA.

Molecular Relaxation Behavior and Isothermal Crystallization above Glass Transition Temperature of Amorphous Hesperetin

The purpose of this paper was to investigate the relaxation behavior of amorphous hesperetin (HRN), using dielectric spectroscopy, and assessment of its crystallization kinetics above glass transition temperature (Tg ). Amorphous HRN exhibited both local (β-) and global (α-) relaxations. β-Relaxation was observed below Tg , whereas α-relaxation prominently emerged above Tg . β-Relaxation was found to be of Johari-Goldstein type and was correlated with α-process by coupling model. Secondly, isothermal crystallization experiments were performed at 363 K (Tg + 16.5 K), 373 K (Tg + 26.5 K), and 383 K (Tg + 36.5 K). The kinetics of crystallization, obtained from the normalized dielectric strength, was modeled using the Avrami model. Havriliak-Negami (HN) shape parameters, αHN and αHN .βHN , were analyzed during the course of crystallization to understand the dynamics of amorphous phase during the emergence of crystallites. HN shape parameters indicated that long range (α-like) were motions affected to a greater extent than short range (β-like) motions during isothermal crystallization studies at all temperature conditions. The variable behavior of α-like motions at different isothermal crystallization temperatures was attributed to evolving crystallites with time and increase in electrical conductivity with temperature.