Study on Sulfamethoxazole-Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties.

Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

Understanding Poor Milling Behavior of Voriconazole from Crystal Structure and Intermolecular Interactions.

The study investigated the milling behavior of voriconazole (VRZ) subjected to particle size reduction using air jet mill at differential air pressures of 5, 6, 7, and 8 bar for five cycles at each pressure. The crystal structure of VRZ was probed for understanding the fracture behavior from crystal packing and intermolecular interactions using molecular modeling tools of attachment energy (Eatt), density functional theory, and energy framework analysis. Upon milling for different cycles, VRZ showed that size reduction from (D90) 20 to 9 µm and 100% particles could not be milled to sizes below 9 µm, with the increase in either the milling intensity or cycle. The milled samples retained the original crystal lattice as evident from consistent melting endotherm (Tm = 130.75 °C); heat of fusion (ΔHf = 96.52 J/g) values; and the plate-shaped morphology. The powder X-ray diffraction pattern of milled samples consistently showed characteristic peaks of stable form B of VRZ. The crystallographic plane (001) was found to be the most prominent slip and the cleavage plane due to least Eatt and weak noncovalent interactions (6.996 kJ/mol) between 3'H and 4'F functional groups of the neighboring planes. The predicted indentation hardness value of 228.67 MPa further indicated toward the plastic nature of VRZ crystals. Corroborating outcomes from the different molecular modeling tools for VRZ, cleavage along the plane (001) was determined to be energetically favorable, whereas cleavage of isotropic 2D molecular sheets was energetically unfavorable. As milling proceeds and crystal reduces in size, contact surface area and overall interaction energy decrease contributing to plastic behavior of the crystal. It was concluded that crystal plasticity and isotropic 2D molecular sheets along with the orientation of particles to the direction of stress and attrition energy during air jet milling are contributing factors for nonuniform size reduction of VRZ particles.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Generation of Ophthalmic Nanosuspension of Prednisolone Acetate Using a Novel Technology.

PURPOSE: Prednisolone Acetate (PAC) is currently marketed as micronized ophthalmic suspension. The microsuspension has poor dose accuracy and efficacy due to aggregation, slow dissolution rate and limited corneal residence. The ophthalmic nanosuspension of PAC shall show enhanced solubility, dissolution rate and corneal adhesion due to small particle size and increased surface area. METHODS: In the current work, we prepared ophthalmic formulation of PAC using a novel, spray drying based technology. Firstly, PAC nanocrystalline solid dispersions (NCSD) were prepared using Mannitol (MAN) as the crystallization inducing excipient and two separate stabilizers, Polyvinyl Alcohol (PAC_MAN_PVA) and Vitamin E Tocopheryl Polyethylene Glycol Sulphosuccinate (PAC_MAN_TPGS). The NCSD was dispersed in an aqueous vehicle to obtain an ophthalmic nanosuspension. RESULTS: The composition, PAC_MAN_PVA (0.3:0.67:0.03%), was pursued due to absence of crystal growth on storage at 40°C/75%RH for 3 months. The resulting nanosuspension showed crystal size, osmolality and viscosity of 590 ± 165 nm, 297 ± 6 mOsm/L and 11 ± 8cP respectively. In 1%w/v SLS media, the nanosuspension showed rapid and complete dissolution of PAC in 120 s. Ex-vivo goat corneal permeation and adhesion study revealed that in comparison to microsuspension, a higher fraction (6.2 times) of nanosuspension adhered to the cornea. Safety studies performed using corneal histopathology and Hen Egg Test- Chorio Allantoic Membrane (HET-CAM) assay showed no physical change in cornea or capillary damage, respectively. CONCLUSIONS: The NCSD can be explored for generation of ophthalmically acceptable nanosuspensions of poorly soluble drugs.

Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution.

Co-crystallization studies were undertaken to improve the solubility of a highly water-insoluble drug febuxostat (FXT), used in the treatment of gout and hyperuricemia. The selection of co-crystal former (CCF) molecules such as 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SAC), 5-nitro isophthalic acid (5-NPH), isonicotinamide (ISNCT), and picolinamide (PICO) was based on the presence of complementary functional groups capable of forming hydrogen bond and the ΔpKa difference between FXT and CCF. A liquid-assisted grinding (LAG) method was successfully employed for the rapid screening of various pharmaceutical adducts. These adducts were characterized based on their unique thermal (differential scanning calorimetry) and spectroscopic (Fourier transform infrared and Raman spectroscopy) profiles. Binary phase diagrams (BPD) were plotted to establish a relationship between the thermal events and adduct formed. Powder X-ray diffraction (PXRD) studies were carried out to confirm the formation of eutectic/co-crystal. Thermogravimetric analysis (TGA) was also performed for the novel co-crystals obtained. The propensity for strong homo-synthons over weak hetero-synthons and strong hetero-synthons over weak homo-synthons during supramolecular growth resulted in the formation of eutectics and co-crystals respectively. FXT:1H-2NPH (1), FXT:4-HBA (1), FXT:SAC (1, 2), and FXT:5-NPH (2-1) gave rise to pure eutectic systems, while FXT:ISNCT (2-1) and FXT:PICO (1) gave rise to novel co-crystals with characteristic DSC heating curves and PXRD pattern. Additionally, the impact of microenvironmental pH and microspeciation profile on the improved dissolution profile of the co-crystals was discussed. Graphical Abstract.

Dual drug nanocrystals loaded microparticles for fixed dose combination of simvastatin and ezetimibe.

Dual drug nanocrystals loaded nano embedded microparticles (DNEMs) were prepared for fixed dose combination of simvastatin (SIM) and ezetimibe (EZE) using NanoCrySP technology. The purpose was to generate nanonized SIM and EZE dispersed in matrix of single crystallization inducing excipient and investigate their in vitro performance. DNEM were prepared using mannitol (MAN) as crystallization inducer (active pharmaceutical ingredients (APIs)/MAN = 3:7 w/w) using spray drying. TPGS (0.1% w/v) was used as surfactant for stabilization of nanocrystals. Crystallinity of DNEM was confirmed by solid-state characterization using DSC and PXRD. Particle size analysis was carried out using Zetasizer® and the Scherrer equation as primary techniques and SEM and TEM as orthogonal techniques. Size of both SIM and EZE in DNEM was close to 600 nm. In vitro performance was assessed using USP apparatus II in 0.025% SLS containing sodium phosphate buffer. Powder dissolution of DNEM increased 1.45 times for SIM and 1.65 times for EZE as compared to their physical mixture in discriminatory medium. MAN did not plasticize SIM or EZE by virtue of its immiscibility with the two drugs. However, MAN helped in inducing crystallization via heterogeneous nucleation. The generated DNEM were stable in terms of assay, polymorphic form and dissolution for 90 days of accelerated storage at 40 °C/75% RH.

Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling.

Poorly soluble weak bases form a significant proportion of the drugs available in the market thereby making it imperative to understand their absorption behavior. This work aims to mechanistically understand the oral absorption behavior for a weakly basic drug, Irbesartan (IRB), by investigating its pH dependent solubility, supersaturation, and precipitation behavior. Simulations performed using the equilibrium solubility could not accurately predict oral absorption. A multi-compartmental biorelevant dissolution testing model was used to evaluate dissolution in the stomach and duodenal compartment and mimic oral drug administration. This model exhibited sustained intestinal supersaturation (2-4-fold) even upon varying flow rates (4 mL/min, 7 mL/min, and mono-exponential transfer) from gastric to intestinal compartment. Simulation of oral absorption using GastroPlus™ and dissolution data collectively predicted plasma exposure with higher accuracy (% prediction error values within ± 15%), thereby indicating that multi-compartment dissolution testing enabled an improved prediction for oral pharmacokinetics of Irbesartan. Additionally, precipitates obtained in the intestinal compartment were characterized to determine the factors underlying intestinal supersaturation of Irbesartan. The solid form of these precipitates was amorphous with considerable particle size reduction. This indicated that following gastric transit, precipitate formation in the amorphous form coupled with an approximately 10 times particle size reduction could be potential factors leading to the generation and sustenance of intestinal drug supersaturation.

Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling.

There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20 mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20 mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.

Investigation of Need of Natural Bioenhancer for a Metabolism Susceptible Drug-Raloxifene, in a Designed Self-Emulsifying Drug Delivery System.

Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%. Self-emulsifying drug delivery system (SEDDS) of RLX was developed using a designed approach and this formulation was loaded with reported bioenhancers: quercetin and piperine. These formulations were tested for improvement in permeability and bioavailability of the RLX. The apparent permeability using everted gut sac (P app) for SEDDS (5.26 ± 1.10 × 10-8 cm/s) was found to be similar to that of SEDDS with bioenhancers (5.11 ± 1.05 × 10-8 cm/s). In oral bioavailability study in rat, SEDDS demonstrated a 4-fold and 2.5-fold higher AUC0-∞ than RLX suspension (control) and marketed product, respectively. No additional improvement in permeability and bioavailability was offered by inclusion of piperine and quercetin (bioenhancers) in the SEDDS.

Oral bioavailability and pharmacodynamic activity of hesperetin nanocrystals generated using a novel bottom-up technology.

In the present study, nanocrystalline solid dispersion (NSD) was developed to enhance the release rate and oral bioavailability of hesperetin (HRN). NSD of HRN was prepared using a novel bottom-up technology platform. It is a spray drying based technology to generate solid particles, containing drug nanocrystals dispersed in small molecule excipients. HRN and mannitol were used in a 5:5 ratio, and an average crystallite size of HRN in NSD with mannitol was found to be 137.3 ± 90.0 nm. An in vitro release study revealed a statistically significant release rate enhancement for HRN nanocrystals (46.3 µg/mL/min) as compared to that of the control (29.5 µg/mL/min). Further, a comparative oral bioavailability study of NSD and control in Sprague-Dawley rats established significant improvement in Cmax and oral bioavailability (AUC0-∞) by 1.79- and 2.25-fold, respectively, for HRN nanocrystals. The findings of oral bioavailability were corroborated by intestinal uptake and Caco-2 cell uptake studies, wherein HRN, when administered in nanocrystalline form, showed higher penetration in intestinal mucosa and higher uptake in Caco-2 cells. Finally, the therapeutic efficacy of HRN nanocrystals was tested by a reactive oxygen species (ROS) generation assay and carrageenan induced anti-inflammatory model. HRN nanocrystals markedly inhibited ROS generation in MCF-7 cells, and carrageenan induced inflammation in rats. The process of NSD formation was found to be based on classical nucleation theory wherein mannitol contributed to NSD formation by acting as a plasticizer and crystallization inducer, and by providing sites for heterogeneous nucleation/crystallization.

Sorption of antimicrobial agents in blow-fill-seal packs.

The present work studies the interaction of methyl paraben (MPB) and propyl paraben (PPB), two widely used antimicrobial agents in multi-dose ophthalmic formulations, with 5 mL, low density polyethylene (LDPE) and polypropylene (PP) blow-fill-seal (BFS) packs, by subjecting the systems to accelerated stability conditions of 40°C/25% RH. The effect of pH, paraben concentration, and relative humidity (RH) on the sorption loss of both the parabens was studied. Additionally, the effects of buffer species and buffer strength on MPB sorption were studied. LDPE packs showed significantly higher loss compared to PP packs which showed < 5% loss in all cases. PPB showed a significantly higher loss (40-50%) than MPB (9-16%) in LDPE. pH (3.0, 5.0, 7.0) did not have a statistically significant effect on sorption. However, concentration, humidity and buffer at pH 7 affected paraben sorption. The application of the power law suggested that the MPB followed non-Fickian diffusion while PPB showed non-Fickian to Case II diffusion in LDPE packs. In conclusion, caution should be exercised while using parabens in LDPE BFS packs because substantial losses of the antimicrobial agent during the shelf-life can compromise the preservative effectiveness against 'in-use' contamination.

Interaction of antimicrobial preservatives with blow-fill-seal packs: correlating sorption with solubility parameters.

The aim of this work was to study the interaction of four commonly used ophthalmic antimicrobial preservatives [benzyl alcohol (BA), chlorbutol (CBL), benzalkonium chloride (BKC), and chlorhexidine gluconate (CG)] with Blow-Fill-Seal (BFS) packs. Effect of packaging material [low-density polyethylene (LDPE), polypropylene (PP)], humidity (25% RH, 75% RH) and concentration (0.5, 1.0, 2.0 mM BA/CBL in LDPE) was studied. BKC and CG gave negligible loss (<4%) in BFS packs over a period of 3 months. BA and CBL, however, gave marked losses in LDPE (ca. 70-90%) and PP (ca. 7-25%) packs. Humidity did not have any effect on the sorption loss of any preservative. Loss of BA switched from Case II to anomalous behavior with increasing initial concentration. A two-stage sorption behavior was inherent at all concentrations. Loss of CBL followed anomalous behavior with biphasic kinetics of loss. It was concluded that all the four preservatives were appropriate for use in PP BFS packs. However, only BKC and CG were amenable to be used in LDPE BFS packs. Lastly, an empirical expression consisting of the "solubility parameter distance" and "molar volume" of preservatives was developed to correlate the preservative loss in LDPE with the physicochemical properties of the preservatives.

Design of Ascorbic Acid Eutectic Mixtures With Sugars to Inhibit Oxidative Degradation.

L-Ascorbic acid (ASC), commonly known as vitamin C, acts as an anti-oxidant in the biological system. It is extensively used as an excipient in pharmaceutical industry, food supplements in fruit juices, and food materials due to its free radicals scavenging activity. Main drawback of ASC is its poor aqueous stability owing to the presence of lactone moiety that is easily oxidized to dehydroascorbic acid and further degraded. To improve aqueous stability and inhibit oxidative degradation, ASC was co-crystallized to constitute binary eutectic compositions with mono and di-saccharides such as glucose, sucrose, lactose, and mannitol. The eutectics were confirmed by their (single) lower melting endotherm compared to ASC and sugars, although Powder X-ray diffraction (PXRD) and Fourier transform Infrared spectroscopy (FT-IR) data confirmed the characteristics of their physical mixture. Scanning electron microscope (SEM) images of the binary eutectics confirmed their irregular morphology. The ASC eutectics exhibited improved shelf-life by 2-5-fold in weakly acidic (pH 5) and neutral (pH 7) aqueous buffer medium, whereas the eutectic with glucose enhanced shelf-life only by 1.1-1.2-fold in acidic medium (pH 3.3 and 4). Notably, stabilizing effect of the sugar eutectics decreased with increasing acidity of the medium. In addition, higher binding energy of the disaccharide eutectics partially supports the aqueous stability order of ASC in the neutral pH medium due to more number of non-bonded interactions than that of monosaccharides.

Role of surface molecular environment and amorphous content in moisture sorption behavior of milled Terbutaline Sulphate.

Milling may cause undesired changes in crystal topology, due to exposure of new facets, their corresponding functional groups and surface amorphization. This study investigated effect of milling induced surface amorphous content and chemical environment on moisture sorption behavior of a model hydrophilic drug, Terbutaline Sulphate (TBS). A Dynamic Vapor Sorption (DVS) based analytical method was developed to detect amorphous content, with LOD and LOQ of 0.41% and 1.24%w/w, respectively. The calibration curve gave a linear regression of 0.999 in a concentration range of 0-16.36%w/w amorphous content plotted against surface area normalized % weight change, due to moisture sorption. TBS was milled using air jet mill at 8 Bars for 3 cycles (D90- 3.46µm) and analyzed using the validated DVS method prior to and post conditioning. The moisture sorption was higher in case of milled unconditioned TBS. Molecular Dynamics Simulation (MDS) was performed to identify the cause for increased moisture sorption due to altered surface environment or amorphous content. The results implied that the new planes and functional groups exposed on milling had negligible contribution to moisture sorption and the higher moisture sorption in milled unconditioned TBS was due to surface amorphization. Conditioning under elevated humidity recrystallized the milling-induced surface amorphous content and led to decreased moisture sorption in milled conditioned TBS.

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 (T(g)) 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.

Effect of sample preparation method on quantification of polymorphs using PXRD.

The purpose of this study was to improve the sensitivity and accuracy of quantitative analysis of polymorphic mixtures. Various techniques such as hand grinding and mixing (in mortar and pestle), air jet milling and ball milling for micronization of particle and mixing were used to prepare binary mixtures. Using these techniques, mixtures of form I and form II of clopidogrel bisulphate were prepared in various proportions from 0-5% w/w of form I in form II and subjected to x-ray powder diffraction analysis. In order to obtain good resolution in minimum time, step time and step size were varied to optimize scan rate. Among the six combinations, step size of 0.05 degrees with step time of 5 s demonstrated identification of maximum characteristic peaks of form I in form II. Data obtained from samples prepared using both grinding and mixing in ball mill showed good analytical sensitivity and accuracy compared to other methods. Powder x-ray diffraction method was reproducible, precise with LOD of 0.29% and LOQ of 0.91%. Validation results showed excellent correlation between actual and predicted concentration with R2 > 0.9999.

Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form.

The conventional "top-down", "bottom-up" and "combination" approaches of generating drug nanocrystals produce a "nanosuspension" (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we used a novel, spray drying-based NanoCrySP technology for the generation of drug nanocrystals in the form of nanocrystalline solid dispersion (NCSD). We hypothesized that the NCSD would require minimal downstream processing since the nanocrystals are obtained in powder form during spray drying. We further compared downstream processing of NS and NCSD of diclofenac acid (DCF) prepared by wet media milling and NanoCrySP technology, respectively. The NS and NCSD were characterized for crystallinity, crystal size, assay and dissolution. The NCSD was physically mixed with 0.3% Aerosil® 200, 1.76% croscarmellose sodium (CCS) and 0.4% sodium stearyl fumarate (SSF) and filled into size 0 hard gelatin capsules. The NS was first wet granulated using Pearlitol® SD 200 (G1 granules) and Celphere® 203 (G2 granules) in a fluidized bed processor, and the resulting granules were mixed using the same extra granular excipients as NCSD and filled into capsules. A discriminatory dissolution method was developed to monitor changes in dissolution behavior due to crystal growth during processing. Cost analysis and comparison of process efficiency was performed using an innovation radar tool. The NS and NCSD were successfully fabricated with a crystal size of 363 ± 21.87 and 361.61 ± 11.78, respectively. In comparison to NCSD-based capsules (65.13%), the G1 and G2 granules showed crystal growth and decrease in dissolution to 52.68% and 48.37%, respectively, in 120 min. The overall cost for downstream processing of NCSD was up to 80% lower than that of NS. An innovation radar tool also concluded that the one-step NanoCrySP technology was more efficient and required less downstream processing than the two-step wet media milling approach for conversion of nanocrystals to OSD.

Evaluation of Different Techniques for Size Determination of Drug Nanocrystals: A Case Study of Celecoxib Nanocrystalline Solid Dispersion.

Celecoxib (CEL) Nanocrystalline Solid Dispersion (CEL_NCSD) was generated by spray drying CEL, mannitol (MAN) and sodium lauryl sulfate (SLS) from a solvent mixture of methanol, acetone and water. The purpose of the work was to determine the size of CEL nanocrystals, investigate agglomeration and inspect dissolution of CEL_NCSD. Size determination was challenging as CEL nanocrystals are embedded in the matrix of MAN. Firstly, neat CEL_NCSD was analyzed using Scherrer equation. Secondly, MAN was dissolved in an aqueous stabilizer medium to selectively measure the size of CEL nanocrystals. Raman Spectra captured in Morphologi G3-ID confirmed the presence of CEL-only particles in the media. This dispersion gave D90 values of 882 ± 170.34 nm in Zetasizer. Discriminatory dissolution studies confirmed total release of 34.61 ± 1.59%, 47.42 ± 0.24%, and 44.61 ± 1.11% at 120 min from a microsuspension (size 3 µm), a nanosuspension (media milled; size 660 nm) and CEL_NCSD, respectively. The dissolution profile of CEL_NCSD was similar to that of a nanosuspension (f2 72.24) instead of a coarse microsuspension. Thus, the present study revealed that optimized sample preparation is critical for the size determination of embedded drug nanocrystals in NCSD. Further, a discriminatory dissolution study substantiated that the size of CEL nanocrystals in CEL_NCSD is well below 1000 nm, thus showing a size-dependent improved dissolution profile.

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.

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.