Strategizing Spray Drying Process Optimization for the Manufacture of Redispersible Indomethacin Nanoparticles Using Quality-by-Design Principles.

The present study adopted a Quality by Design (QbD) approach to spray dry indomethacin nanosuspension (IMC-NS) consisting of HPC-SL, poloxamer 407, and lactose monohydrate. The Box-Behnken Design was used to systematically evaluate the effects of inlet temperature, aspiration rate, and feed rate on the critical quality attributes (CQAs) [redispersibility index (RDI; minimize), % yield (maximize), and % release at 15 min (maximize)] of the indomethacin spray dried nanosuspension (IMC-SD-NS). To identify significant main and quadratic effects, two-way interactions, and create a predictive model for the spray drying process, regression analysis and ANOVA were utilized. Following optimization, the IMC-SD-NS was analyzed for its physicochemical properties using X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution studies. Statistical analysis revealed significant independent variables, including inlet temperature, feed rate, and aspiration rate, that critically impacted the solidified end product's RDI, % yield, and % release at 15 min. The models developed for critical quality attributes (CQAs) were significant at a p-value of 0.05. The crystalline state of IMC was maintained in the solidified product, as confirmed by XRPD, and no interactions were observed between IMC and the excipients as evaluated by FTIR. In vitro dissolution studies showed improved dissolution rate for the IMC-SD-NS (3.82-fold increase in overall drug release), which may be attributed to the readily redispersible nanosized drug particles. The implementation of a well-designed study, utilizing Design of Experiments (DoE) methodology, played a crucial role in the development of a highly effective spray drying process.

Modeling of Adhesion in Tablet Compression at the Molecular Level Using Thermal Analysis and Molecular Simulations.

The molecular basis of adhesion leading to sticking was investigated by exploring the correlation between thermal analysis and molecular simulations. It is hypothesized that intermolecular interactions between a drug molecule and a punch face are the first step in the adhesion process and the rank order of adhesion during tablet compression should correspond to the rank order of the energies of these interactions. In the present study, the sticking propensity was investigated using ibuprofen, flurbiprofen, and ketoprofen as model substances. At the intermolecular level, a thermal analysis model was proposed as an experimental technique to estimate the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen in a DSC aluminum pan. The linear relationship was established between the enthalpy of vaporization and sample mass to demonstrate the accuracy of the instruments used. The threshold mass for ibuprofen, flurbiprofen, and ketoprofen was determined to be 107, 112, and 222 µg, respectively, after three replicate measurements consistent with the experimental results. Ketoprofen showed a 2-fold higher threshold mass compared to ibuprofen and flurbiprofen, which predicts that ketoprofen should have the highest sticking propensity. Computationally, the rank order of the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen with the metal surface was simulated to be -75.91, 44.75, and -96.91 kcal/mol, respectively, using Materials Studio. The rank order of the interaction between the drug molecule and the iron superlattice decreases in the order ketoprofen > ibuprofen > flurbiprofen. The results indicate that the thermal model can be successfully implemented to assess the sticking propensity of a drug at the molecular level. Also, a new molecular simulation script was successfully applied to determine the interaction energy of the drug molecule upon contact with iron.

Molecular Insights into Warfarin Sodium 2-Propanol Solvate Solid Form Changes and Disproportionation Using a Low Volume Two-Stage Dissolution Approach.

The current research work focuses on understanding the reported discrepancies and our observations in the dissolution profiles of warfarin sodium tablets and potential patient-based failure modes during oral warfarin therapy. It was hypothesized that freely soluble crystalline warfarin sodium (WARC) at first transforms into noncrystalline warfarin sodium (WARNC) under stress conditions. The WARC → WARNC conversion facilitates the rapid formation of the poorly soluble unionized form, which could lead to dissolution failures and potential poor in vivo performance. Depressed warfarin concentrations locally in the gastrointestinal tract (GIT) may in turn lead to inadequate absorption and thereby affect bioavailability. A low volume two-stage dissolution method was developed to mimic in vivo GIT conditions. Warfarin sodium tablets exposed to room temperature and 75% relative humidity for 1 week showed approximately 23% decrease in drug release. The decline in drug release supports the hypothesis that WARNC is converted to the unionized form faster than WARC does under the same conditions. Solid state characterization (powder X-ray diffractometry and differential scanning calorimetry) data demonstrated the disproportionation of warfarin sodium to unionized warfarin after solubility and dissolution studies. The findings support the hypothesis and a possible failure mode of warfarin sodium tablets. This work is a second case study from our laboratory on narrow therapeutic index drug products in which the instability of the solid state of the drug substance is potentially responsible for observed clinical failures.

Systematic implementation of quality-by-design (QbD) to develop NSAID-loaded nanostructured lipid carriers for ocular application: preformulation screening studies and statistical hybrid-design for optimization of variables.

The objective of the present project was to develop and optimize the Ibuprofen (IBU)-loaded nanostructured lipid carrier (IBU-NLCs) for sustained-release ocular drug delivery using a quality-by-design (QbD) approach. The BCS class II drug IBU was selected as the model drug for the preparation of IBU-NLCs by melt-emulsification and ultrasonication technique. Extensive preformulation screening of the components of NLC dispersion (i.e. solid and liquid lipid, surfactants, and osmolality agents) was performed. From the various lipids screened, Dynasan®114 and Miglyol®840 were selected as the most suitable solid and liquid lipid, respectively. These lipids, at a matrix ratio of 6:4, demonstrated a lower melting-point and crystallinity-index based on DSC, XRD, and compatibility studies. Various surfactants were evaluated, and among them, Kolliphor®HS15 demonstrated lower z-average particle size (PS) and polydispersity index (PDI), while Kolliphor®P188 resulted in a zeta potential (ZP) <-20 mV. Glycerol was selected from various osmolality agents due to its negligible effects on physicochemical properties of the optimized formulation. A Plackett-Burman design (PBD) was used for the initial screening of the critical variables, followed by a Box-Behnken design (BBD) for further optimization of the NLC dispersion. The optimized formulation demonstrated the PS of 147 nm, with narrow PDI (0.159), ZP of -25.7 mV, and an entrapment efficiency (EE) of 97.89%. In vitro diffusion of IBU from the optimized IBU-NLC dispersion showed a sustained-release of ∼51% for up to 12 h. Preformulation studies and a statistical hybrid-design approach was effectively applied to incorporate IBU in NLCs, resulting in a robust ophthalmic formulation with superior physicochemical properties.

Influence of punch geometry (head-flat diameter) and tooling type ('B' or 'D') on the physical-mechanical properties of formulation tablets.

The presented study assessed the influence of punch geometry (head-flat [HF] diameter) and tooling type ('B' or 'D') on the physical-mechanical properties of tablets prepared by direct-compression of two guaifenesin (25% or 40% w/w) formulations. Tablets of both formulations were prepared on instrumented, single-layer, rotary tablet press using 10 mm, flat-faced, 'B' or 'D'-type tooling with different HF diameters, and compression forces (CF) ranging from 5 to 25 kN with 5 kN increments. The tablets were evaluated for dimensions, weight variation, tensile strength (TS), friability, and capping index. In general, tablets prepared using 'D' tooling showed a significantly (p < 0.05) higher TS compared to those prepared using 'B' tooling, likely due to higher dwell-times associated with 'D' tooling. Formulations containing 25% w/w guaifenesin showed a significantly (p < 0.05) higher TS compared to those containing 40% w/w guaifenesin, at given compression CF, punch geometry, or tooling type. This could be due to the higher ratio of Prosolv® SMCC contributing to the compressibility. For both formulations compressed using 'B' tooling, differences in TS profiles were observed between different HF tooling. The TS of these tablets increased significantly with increasing HF diameter. For formulations compressed using 'D' tooling, this trend was observed only up to a CF of 15 kN, beyond which the TS plateaued, possibly due to work-hardening of the formulation at higher CF. These formulations also exhibited capping at CF above 15 kN and with higher HF diameters. The study showed a significant influence of punch geometry and tooling type on the physical properties of tablets.

A Mechanistic Approach To Model the Compression Cycle of Different Toolings Based on Compression Roller Interactions.

The aim of the current work was to model and understand the mechanical interactions of tooling heads with compression rollers during tableting. Binary direct compression blends of Prosolv® SMCC with 0.5% w/w magnesium stearate and ternary blends with 30% w/w acetaminophen were used. Tablet compression was performed using an instrumented Riva Piccola press with 10 mm round flat face D- and B-type TSM domed punches. Five punches were used for the study with varying dimensions of head flats. Strain rate studies were carried out at 12.5, 25, 50, and 75 revolutions of turret per minute (RPM) and a compaction profile was performed at compression pressures of 50, 100, 150, and 200 MPa. Tablet weight, thickness, and tensile strength were evaluated. Compression raw data was used to model the punch interactions. A MATLAB program was created to model the head profiles based on their dimensions, punch tip separation, vertical velocity, and pitch circle diameter of the press. Tablets compressed with no head flats were the weakest and showed less strain rate sensitivity. Tensile strengths increased linearly with the head flat dimensions. Also, difference in loading times due to roll movement during compression was evaluated. Capping was observed in tablets compressed at 75 RPM from the ternary blend containing 30% acetaminophen. However, punches with zero head flat showed no capping at these speeds. Also, B-type tooling showed relatively less capping tendency. This work shows that dwell time effect on tablet properties is based on the punch head flat region and the punch head interactions with the rollers.

A quality-by-design study to develop Nifedipine nanosuspension: examining the relative impact of formulation variables, wet media milling process parameters and excipient variability on drug product quality attributes.

Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was investigated in the present study. Nifedipine, a poorly water soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL Soluplus®, Kollidon® VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC and poloxamer 407 was found to be most stable with the lowest mean particle size as compared with the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution study. Results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility and rapid in vitro dissolution as compared with pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.

Influence of processing methods on physico-mechanical properties of Ibuprofen/HPC-SSL formulation.

The objective of the present study was to investigate the influence of processing methods on the physical and mechanical properties of formulations containing Ibuprofen and HPC-SSL. The powder blends, containing Ibuprofen and HPC-SSL in ratio of 9:0.5, were processed using melt granulation (MG) by hot melt extrusion (HME) and wet granulation (WG) by high shear mixer. Formulated granules and powder blends were compressed into round flat faced tablets using Riva Piccola tablet press. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) studies proved that granulation process did not significantly alter the crystallinity of Ibuprofen, however, particle density and flow properties were significantly improved. Scanning electron microscopy (SEM) and particle size analysis corroborate with the findings that the flow characteristics of granules from MG were relatively superior to other formulations. Formulations were investigated for out-of-die compaction behaviour using Heckel, Kawakita, and CTC profile analysis. Detailed examination revealed that all three formulations differed in particle size due to the granulation, thus conferring to different compaction behaviour. In WG and MG, granulation offered an increase in particle size resulting in high compressibility along with deformation at low compression pressure. This results into low yield pressure, low yield strength, and higher densification, as compared with dry blend. The current work provides an insight into factors affecting physical and mechanical properties tablets, which can facilitate the rational selection of suitable change in processing method instead of changing excipients.

Investigating a Novel Hot Melt Extrusion-Based Drying Technique to Solidify an Amorphous Nanosuspension Using Design of Experiment Methodology.

The hot melt extrusion (HME) technology was explored and optimized to solidify an amorphous nanosuspension using Quality by Design (QbD) methodology. A design of experiments (DoE) approach was used to perform a set of 15 experiments, varying independent variables (feed rate, input temperature, and screw speed) within a design space. Redispersibility index (RDI), moisture content, and process yield constituted the critical quality attributes (CQAs) of the experimental design. Regression analysis and ANOVA were employed to identify and estimate significant main effects and two-way interactions, and model the process of HME drying for predictive purposes. The optimized HME-dried end product was characterized for physicochemical properties using differential scanning calorimetry (DSC), X-ray powder diffractions (XRPD), polarized light microscopy (PLM), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution studies. The statistical analysis reveals feed rate and input temperature as significant independent variables, critically influencing RDI and moisture content of solidified end product. The model developed for process yield was insignificant at a p-value of 0.05. The API retained its amorphous nature after the extrusion process which was confirmed using DSC and XRPD techniques. PLM was unsuitable to differentiate and determine crystallinity of drug moiety in the presence of a semi-crystalline bulking agent, microcrystalline cellulose (MCC). In vitro dissolution study depicted solubility and dissolution enhancement for HME-dried amorphous nanosuspension in both the dissolution media which can be attributed to amorphous nature of nanosized drug particles. A well-designed study implemented by DoE aided in developing a robust and novel HME technique to dry aqueous nanosuspension.

Determination of Degradation Kinetics and Effect of Anion Exchange Resin on Dissolution of Novel Anticancer Drug Rigosertib in Acidic Conditions.

Rigosertib is a novel anticancer drug in clinical development by Onconova therapeutics, Inc. Currently, it is in pivotal phase III clinical trials for myelodysplastic syndrome (MDS) patients. Chemically, it is a sodium salt of weak acid with low solubility in lower pH solutions. In the preliminary studies, it was found that rigosertib is unstable in acidic conditions and forms multiple degradation products. In this research, drug degradation kinetics of rigosertib were studied in acidic conditions. Rigosertib follows pseudo-first-order general acid catalysis reaction. Cholestyramine, which is a strong anion exchange resin, was used to form complex with drug to improve stability and dissolution in acidic conditions. Drug complex with cholestyramine showed better dissolution profile compared to drug alone. Effect of polyethylene glycol was investigated on the release of drug from the drug resin complex. Polyethylene glycol further improved dissolution profile by improving drug solubility in acidic medium.

Investigate the effect of solvents on wet granulation of microcrystalline cellulose using hydroxypropyl methylcellulose as a binder and evaluation of rheological and thermal characteristics of granules.

Wet granulation is the most commonly used technique in the pharmaceutical industry for delivering oral solid dosage forms. In wet granulation, the binder solvent is one of the critical factors affecting granule properties. In the current study, an attempt was made to investigate the effect of solvents (aqueous and hydro-alcoholic) on thermal and flow properties of Microcrystalline Cellulose (MCC) granules prepared using two different grades of Hydroxypropyl Methylcellulose (HPMC), which served as an effective binder. The granulation endpoint was evaluated using thermal effusivity sensor. Rheometer and Modulated Differential Scanning Calorimetry (mDSC) was used to study the flow and thermal properties of wet and dried granules. Furthermore, physical characterization was carried out by granule strength, particle size distribution and tablet hardness for all granules under the study. Thermal effusivity sensor results indicate 55% w/w concentration of binder solution as the endpoint by measuring thermal effusivity for both binders. Additionally, powder rheometer results show that the wet granules of hydro-alcoholic batches show greater resistance to flow whereas the dried granules display excellent flow characteristics as evident from Basic flowability energy values and specific energy values. Permeability results suggest that the granules formed with hydro-alcoholic binder solvent exhibit better porosity and permeability. Tablet hardness data showed that tablets formulated using hydro-alcoholic solvent granules have greater hardness than tablets formulated using water based solvent granules. The granule strength for water based granules is relatively higher than that of hydro-alcoholic based granules. mDSC thermograms show a sharp rise in enthalpy value at 55% w/w binder solution which is indicative of a more significant amount of solvent being present on the surface of granules and formation of optimal granules. To summarize, we have determined a technique to measure endpoint determination and simultaneously investigate the role of solvent systems on the rheology of MCC granules, which could assist in selecting an appropriate solvent system for granulation.

To Study Capping or Lamination Tendency of Tablets Through Evaluation of Powder Rheological Properties and Tablet Mechanical Properties of Directly Compressible Blends.

Air entrapment efficiency of the powders is one of the main factors leading to occurrence of capping or lamination tendency of tablets manufactured from the directly compressible powder blends. The purpose of the current research was to study this underlying cause leading to occurrence of capping or lamination of tablets through evaluation of powder rheological properties. Powder blends were prepared by addition of 0% w/w to 100% w/w of individual active pharmaceutical ingredient (API) [two model API: acetaminophen (APAP) and ibuprofen (IBU)] with microcrystalline cellulose without and with 0.5% w/w Magnesium Stearate as lubricant. Powder rheological properties were analyzed using FT4 Powder Rheometer for dynamic, bulk, and shear properties. Tablet mechanical properties of the respective blends were studied by determining the ability of the material to form tablet of specific strength under applied compaction pressure through tabletability profile. The results showed that powder rheometer distinguished the powder blends based on their ability to relieve entrapped air along with the distinctive flow characteristics. Powder blend prepared with increasing addition of APAP displayed low powder permeability as compared to IBU blends with better powder permeability, compressibility and flow characteristics. Also, lubrication of the APAP blends did not ease their ability to relieve air. Tabletability profiles revealed the potential occurrence of capping or lamination in tablets prepared from the powder blends with high APAP content. This study can help scientist to understand tableting performance at the early-developmental stages and can avoid occurrence capping and lamination of tablets.

Influence of spray drying and dispersing agent on surface and dissolution properties of griseofulvin micro and nanocrystals.

The purpose for the current research is to compare and evaluate physiochemical properties of spray-dried (SD) microcrystals (MCs), nanocrystals (NCs), and nanocrystals with a dispersion agent (NCm) from a poorly soluble compound. The characterization was carried out by performing size and surface analysis, interfacial tension (at particle moisture interface), and in-vitro drug dissolution rate experiments. Nanosuspensions were prepared by media milling and were spray-dried. The SD powders that were obtained were characterized morphologically using scanning electron microscopy (SEM), polarized light microscopy (PLM), and Flowchem. Solid-state characterization was performed using X-ray powder diffraction (XRPD), Fourier transfer infrared spectroscopy (FT-IR), and differential scanning calorimetry (DSC) for the identification of the crystalline nature of all the SD powders. The powders were characterized for their redispersion tendency in the water and in pH 1.2. Significant differences in redispersion were noted for both the NCs in both dissolution media. The interfacial tension for particle moisture interface was determined by applying the BET (Braunauer-Emmett-Teller) equation to the vapor sorption data. No significant reduction in the interfacial tension was observed between MCs and NCs; however, a significant reduction in the interfacial tension was observed for NCm at both 25 °C and 35 °C temperatures. The difference in interfacial tension and redispersion behavior can be attributed to a difference in the wetting tendency for all the SD powders. The dissolution studies were carried out under sink and under non-sink conditions. The non-sink dissolution approach was found suitable for quantification of the dissolution rate enhancement, and also for providing the rank order to the SD formulations.

Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407.

Aim of current research was to prepare ibuprofen-poloxamer 407 binary mixtures using fusion method and characterize them for their physicochemical and performance properties. Binary mixtures of ibuprofen and poloxamer were prepared in three different ratios (1:0.25, 1:0.5, and 1:0.75, respectively) using a water-jacketed high shear mixer. In vitro dissolution and saturation solubility studies were carried out for the drug, physical mixtures, and formulations for all ratios in de-ionized water, 0.1 N HCl (pH = 1.2), and phosphate buffer (pH = 7.2). Thermal and physical characterization of samples was done using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRD), and infrared spectroscopy (FTIR). Flow properties were evaluated using a powder rheometer. Maximum solubility enhancement was seen in acidic media for fused formulations where the ratio 1:0.75 had 18-fold increase. In vitro dissolution studies showed dissolution rate enhancement for physical mixtures and the formulations in all three media. The most pronounced effect was seen for formulation (1:0.75) in acidic media where the cumulative drug release was 58.27% while for drug, it was 3.67%. Model independent statistical methods and ANOVA based methods were used to check the significance of difference in the dissolution profiles. Thermograms from mDSC showed a characteristic peak for all formulations with Tpeak of around 45°C which suggested formation of a eutectic mixture. XRD data displayed that crystalline nature of ibuprofen was intact in the formulations. This work shows the effect of eutectic formation and micellar solubilization between ibuprofen and poloxamer at the given ratios on its solubility and dissolution rate enhancement.

To Evaluate the Effect of Solvents and Different Relative Humidity Conditions on Thermal and Rheological Properties of Microcrystalline Cellulose 101 Using METHOCEL™ E15LV as a Binder.

The solvent used for preparing the binder solution in wet granulation can affect the granulation end point and also impact the thermal, rheological, and flow properties of the granules. The present study investigates the effect of solvents and percentage relative humidity (RH) on the granules of microcrystalline cellulose (MCC) with hydroxypropyl methyl cellulose (HPMC) as the binder. MCC was granulated using 2.5% w/w binder solution in water and ethanol/water mixture (80:20 v/v). Prepared granules were dried until constant percentage loss on drying, sieved, and further analyzed. Dried granules were exposed to different percentage RH for 48 h at room temperature. Powder rheometer was used for the rheological and flow characterization, while thermal effusivity and differential scanning calorimeter were used for thermal analysis. The thermal effusivity values for the wet granules showed a sharp increase beginning 50% w/w binder solution in both cases, which reflected the over-wetting of granules. Ethanol/water solvent batches showed greater resistance to flow as compared to the water solvent batches in the wet granule stage, while the reverse was true for the dried granule stage, as evident from the basic flowability energy values. Although the solvents used affected the equilibration kinetics of moisture content, the RH-exposed granules remained unaffected in their flow properties in both cases. This study indicates that the solvents play a vital role on the rheology and flow properties of MCC granules, while the different RH conditions have little or no effect on them for the above combination of solvent and binder.

To prepare and characterize microcrystalline cellulose granules using water and isopropyl alcohol as granulating agents and determine its end-point by thermal and rheological tools.

Microcrystalline cellulose (MCC-102) is one of the most commonly used excipient in the pharmaceutical industry. For this research purpose, authors have developed a different technique to determine the end point for MCC-102 using water and isopropyl alcohol 70% (IPA) as granulating agent. Wet and dry granules obtained were characterized for their flow properties using the powder rheometer and thermal analysis. Powder rheometer was used to measure basic flowability energy (BFE), specific energy (SE), percentage compressibility, permeability and aeration. Thermal analysis includes effusivity and differential scanning calorimetry (DSC) measurements. BFE and SE results showed water granules requires high energy as compared to IPA granules. Permeability and compressibility results suggest IPA forms more porous granules and have better compressibility as compared to water granules. Hardness data reveals interesting phenomena in which as the amount of water increases, hardness decreases and vice-versa for IPA. Optimal granules were obtained in the range of 45-55% w/w. DSC data supported the formation of optimal granules. Empirical measurements like angle of repose did not reveal any significant differences between powder flow among various granules. In this paper, with the help of thermal effusivity and powder rheology we were able to differentiate between various powder flows and determine the optimal range for granule formation.

To study physical compatibility between dibasic calcium phosphate and cohesive actives using powder rheometer and thermal methods.

AIM: An attempt is made to provide better understanding of the compatibility aspect of excipients with different properties of active pharmaceutical ingredient (API) using various rheological, thermal and morphological studies conducted on binary mixtures of Dibasic Calcium Phosphate anhydrous (DCP-A) and Dibasic Calcium Phosphate dihydrate (DCP-D) forms with cohesive API's (Acetaminophen and Aspirin). METHOD: Binary mixtures of DCP's were prepared by addition of 0% w/w to 50% w/w of the API in each powder blend. Powder rheological analysis were conducted using FT4 powder rheometer, rotational shear cell and empirical approaches such as angle of repose (AOR), Hausner ratio (HR) and Carr's index (CI). Thermal analysis was conducted using differential scanning calorimetry (DSC) and thermal effusivity. Morphological studies were conducted using Scanning Electron Microscopy (SEM) to determine the fundamental differences between powder materials. Result/Conclusions: Powder rheometer showed distinctive understanding in the flowability behavior of binary mixtures with addition of increasing proportion of API's than empirical approaches. Thermal approaches revealed the potential interaction of water of crystallization DCP-D while such interaction was absent in DCP-A. Binary mixtures prepared using DCP-D were better flowable while blends containing DCP-A were better in stability (physical), compressibility and permeability. This study allows the scientist to understand the powder packing of different blends with their flowability and compressibility parameter and helps selection of appropriate form of hydrate for relevant API.

To evaluate the change in release from solid dispersion using sodium lauryl sulfate and model drug sulfathiazole.

The solubility of drugs remains one of the most challenging aspects of formulation development. There are numerous ways to improve the solubility of drugs amongst which the most promising strategy is solid dispersion. Different ratios of sulfathiazole: PVP-K29/32: sodium lauryl sulfate (SLS) were prepared (1:1:0.1, 1:1:0.5, 1:1:1) and various methods were employed to characterize the prepared solid dispersions, namely modulated differential scanning calorimeter, X-ray powder diffraction, Fourier Transformed Infrared Spectroscopy and dissolution studies. Lack of crystallinity was observed in internal and external systems suggesting a loss of crystallinity, whereas the physical mixtures showed a characteristic peak of sulfathiazole. In vitro dissolution results clearly showed that the incorporation of a relatively small amount of surfactants (5, 20 or 33% w/w) into a solid dispersion can improve its dissolution rates compared to binary solid dispersion (SD) alone and pure sulfathiazole. In all ratios solid dispersion internal shows a higher dissolution rate compared to a physical mixture and solid dispersion external which suggests that the way that the surfactant is incorporated into the solid dispersion plays an important role in changing the solubility of a drug. The solubilization mechanism is mainly responsible for this higher dissolution rate when we incorporate the SLS in SD.

Evaluation of colloidal solid dispersions: physiochemical considerations and in vitro release profile.

Colloidal solid dispersion is an innovative breakthrough in the pharmaceutical industry that overcomes the solubility-related issue of poorly soluble drugs by using an amorphous approach and also the stability-related issue by means of a complex formation phenomenon using different carrier materials. In the present study, a newly developed adsorption method is introduced to incorporate a high-energy sulfathiazole-polyvinylpyrrolidone (Plasdone® K-29/32) solid dispersion on porous silicon dioxide (Syloid® 244FP). Different ternary systems of sulfathiazole-Plasdone® K-29/32-Syloid® 244FP were prepared (1:1:2, 1:1:3, and 1:2:2) and categorized depending on the mechanism by which Syloid® 244FP was incorporated. Modulated differential scanning calorimetry (MDSC), X-ray diffraction, Fourier transform infrared spectroscopy, and in vitro dissolution studies were conducted to characterize the ternary systems. The X-ray diffraction and MDSC data showed a lack of crystallinity in all internal and external ternary systems, suggesting a loss of the crystallinity of sulfathiazole compared to the physical mixtures. USP apparatus II was used to measure the in vitro dissolution rate of the prepared systems at 75 rpm in different media. The dissolution rate of the optimum ratio (1:2:2) containing an internal ternary solid dispersion system was found to be three times higher than that of the external and physical systems. Thus, the porous silicon dioxide incorporated into the conventional binary solid dispersion acted as a carrier to disperse the complex and increase the dissolution rate.

Evaluating the effect of glidants on tablet sticking propensity of ketoprofen using powder rheology.

Punch sticking has been a leading drawback that has challenged successful tablet manufacturing since its initial conception. Due to the capricious nature of the complication, this can arise during any phase of the development process. Even now, identifying such a problem is a prerequisite during the initial stage of development. The present study evaluated the role of Aerosil®200, talc, and Syloid®244 as glidants in varying amounts ranging from 0.0 percent to 2.0 percent w/w on tablets sticking relatively to five different metal surfaces, with ketoprofen as the model drug. Powder rheology is a predictable technique used to calculate the sticking index. The sticking index of each formulation in comparison to each metal coupon was identified by calculating the kinematic angle of internal friction and the angle of wall friction using the shear cell test and wall friction test, respectively. Interestingly, glidants were found to reduce the sticking propensity of the powder blend in a concentration-dependent manner. In addition, the compression study validated the expected sticking tendency ranking order. According to the research data, the sticking index could effectively be utilized to envisage the possibility of tablet sticking, i.e., by selecting the formulation's excipient and their percentages or selecting appropriate punched metal surfaces in the tableting process.