Design of Experiments-Driven Optimization of Spray Drying for Amorphous Clotrimazole Nanosuspension.

This study employed a Quality by Design (QbD) approach to spray dry amorphousclotrimazole nanosuspension (CLT-NS) consisting of Soluplus® and microcrystallinecellulose. Using the Box-Behnken Design, a systematic evaluation was conducted toanalyze the impact of inlet temperature, % aspiration, and feed rate on the criticalquality attributes (CQAs) of the clotrimazole spray-dried nanosuspension (CLT-SDNS). In this study, regression analysis and ANOVA were employed to detect significantfactors and interactions, enabling the development of a predictive model for the spraydrying process. Following optimization, the CLT-SD-NS underwent analysis using Xraypowder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), Dynamic Scanning Calorimetry (DSC), and in vitro dissolution studies. The resultsshowed significant variables, including inlet temperature, feed rate, and aspiration rate,affecting yield, redispersibility index (RDI), and moisture content of the final product. The models created for critical quality attributes (CQAs) showed statistical significanceat a p-value of 0.05. XRPD and DSC confirmed the amorphous state of CLT in theCLT-SD-NS, and FTIR indicated no interactions between CLT and excipients. In vitrodissolution studies showed improved dissolution rates for the CLT-SD-NS (3.12-foldincrease in DI water and 5.88-fold increase at pH 7.2 dissolution media), attributed torapidly redispersing nanosized amorphous CLT particles. The well-designed studyutilizing the Design of Experiments (DoE) methodology.

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.

Developing a Formulation Strategy Coupled with PBPK Modeling and Simulation for the Weakly Basic Drug Albendazole.

Albendazole (ABZ) is a weakly basic drug that undergoes extensive presystemic metabolism after oral administration and converts to its active form albendazole sulfoxide (ABZ_SO). The absorption of albendazole is limited by poor aqueous solubility, and dissolution is the rate-limiting step in the overall exposure of ABZ_SO. In this study, PBPK modeling was used to identify formulation-specific parameters that impact the oral bioavailability of ABZ_SO. In vitro experiments were carried out to determine pH solubility, precipitation kinetics, particle size distribution, and biorelevant solubility. A transfer experiment was conducted to determine the precipitation kinetics. A PBPK model for ABZ and ABZ_SO was developed using the Simcyp™ Simulator based on parameter estimates from in vitro experiments. Sensitivity analyses were performed to assess the impact of physiological parameters and formulation-related parameters on the systemic exposure of ABZ_SO. Model simulations predicted that increased gastric pH significantly reduced ABZ absorption and, subsequently, ABZ_SO systemic exposure. Reducing the particle size below 50 µm did not improve the bioavailability of ABZ. Modeling results illustrated that systemic exposure of ABZ_SO was enhanced by increasing solubility or supersaturation and decreasing the drug precipitation of ABZ at the intestinal pH level. These results were used to identify potential formulation strategies to enhance the oral bioavailability of ABZ_SO.

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.

Understanding the Impact of Multi-factorial Composition on Efficient Loading of the Stable Ketoprofen Nanoparticles on Orodispersible Films Using Box-Behnken Design.

The purpose of the present study was to prepare Orodispersible films (ODFs) loaded with ketoprofen nanoparticles (KT-NP). The Box-Behnken design was constructed in developing and optimizing the KTF-NP-ODFs. The effect of independent variables: Soluplus® concentration (X1, stabilizer), Tween 80 concentration (X2, surfactant), and KTF concentration (X3, drug) were studied on the dependent variables: particle size (PS, Y1), zeta potential (ZP, Y2), and the polydispersity index (PDI, Y3) of the NPs, as well as on the tensile strength (TS, Y4) and permeability coefficient (PC, Y5) of the KTF-NP-ODFs. Hydroxypropyl methylcellulose (HPMC E15) and polyethylene glycol (PEG 400) were used as the film former polymer and plasticizer, respectively, and their concentrations were kept constant for all formulations. KTF-NPs were prepared by antisolvent precipitation technology. This was followed by the addition of HPMC E15 and PEG 400 to prepare the ODFs using the solvent-casting method. The PS, PDI, and ZP for all the formulations were found in the range of 94 nm to 350 nm, 0.09 to 0.438, and -21.83 mV to -8.03 mV, respectively. The TS and PC of the prepared KTF-NP-ODFs were found between 1.21 MPa to 3.93 MPa and 3.12 × 10-4 cm/h to 34.23 × 10-4 cm/h, respectively. The amorphous nature of the KTF-NP in the ODFs was confirmed by the absence of characteristic crystalline peaks and endothermic events of KTF in X-ray diffraction (XRD) and modulated differential scanning calorimetry (mDSC), respectively. The optimized formulation showed Ì´ 4 times higher permeability as compared to the pure KTF. In addition, the dissolution of pure KTF and the optimized KTF-NP-ODF in pH 1.2 at the end of 60 min was found to be Ì´ 30% and Ì´ 95%, respectively. Conclusively, KTF-NP-ODFs can be a promising drug delivery system to counter the issues related to dysphagia and bypass the common side effects, such as the gastric irritation associated with NSAIDs like KTF.

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.

Predicting lubricants effect on tablet sticking using ketoprofen as model drug and evaluating sticking propensity using different metals and powder rheology.

Tablet sticking occurrence is a persistent, costly, and time-consuming problem that needs to be resolved. Predicting the sticking tendency of a new formulation has been very difficult during the development batches because of short runs and limited data. A model formulation comprising ketoprofen and microcrystalline cellulose was used to predict the effect of magnesium stearate and sodium stearyl fumarate on the occurrence of tablet sticking relative to different punch metals. Lubricant amounts were varied from 0.0% to 2.0 %w/w. Five different metal coupons were used to represent punch metals. The sticking index (SI) of each formulation relative to each metal coupon was determined by measuring angle of internal friction and angle of wall friction by performing shear cell test and wall friction test, respectively. The SI was used to predict each formulation's sticking tendency rank order relative to metal coupon. Both lubricants show a decrease in the powder blend's sticking propensity with increased lubricant concentration. The predicted sticking propensity rank order was then validated by the compression study. The result suggests that the SI can be used to predict tablet sticking, such as by changing the composition of the formulation or changing the punch metal during tablet compression.

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.

Protocol development, validation, and troubleshooting of in-situ fiber optic bathless dissolution system (FODS) for a pharmaceutical drug testing.

Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS). In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Dissolution runs were conducted at 37 ± 0.2 °C using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. The linearity determination method was developed using five concentration levels between 25-125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation). Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.

Stability of Insulin Detemir Injection in Different Primary Packaging Systems at Room Temperature.

PURPOSE: To assess the stability of insulin detemir at controlled room temperature (RT) at 25°C in different packaging systems over 7 days. METHODS: The degradation characteristics of insulin detemir were determined based on the assay results in different packaging systems (pinhole glass vial, closed glass vial, glass syringe, and plastic syringe) at RT using a reverse-phase high-performance liquid chromatography (HPLC) assay method for insulin injection. Each packaging system was compared to insulin detemir stored in the original packaged closed glass vial at 2°C to 8°C. RESULTS: Insulin detemir stored in a closed glass vial and a glass syringe showed minor degradation at the end of day 7 (98.96% ± 1.49% and 99.78% ± 0.10%, respectively). Insulin detemir stored in plastic syringe decreased to 94.90% ± 2.50% by day 3 and to 93.52% ± 0.29% by day 7. Storage in pin-hole glass vial showed an increase in the assay (152.13% ± 0.12%) by day 7. CONCLUSION: Stability studies in different packaging systems demonstrated that insulin detemir remained stable for at least 7 days in a closed glass vial or glass syringe, but for only 3 days in a plastic syringe at RT. This study will allow pharmacists in the hospital setting to deliver patient-specific insulin doses into an insulin syringe with confidence in the stability.

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.

Effects of compaction pressure, speed and punch head profile on the ultrasonically-extracted physical properties of pharmaceutical compacts.

Despite a well-established manufacturing-process understanding, tablet quality issues are frequently encountered during various stages of drug-product development. Compact breaking force (tensile strength), capping and friability are among the commonly observed characteristics that determine the integrity, quality and manufacturability of tablets. In current study, a design space of the compaction pressure, compaction speed and head flat types is introduced for solid dosage compacts prepared from pure silicified microcrystalline cellulose, a popular tableting excipient. In the reported experiments, five types of head flat types at six compaction pressure levels and two compaction speeds were employed and their effects on compact mechanical properties evaluated. The mechanical properties of the tablets were obtained non-destructively. It is demonstrated these properties correlate well with compact porosity and tensile strength, thus their availability is of practical value. The reported mechanical properties are observed to be linearly sensitive to the tableting speed and compaction pressure, and their dependency on the head-flat profile, while clearly visible in the presented waveforms, was found to be nonlinear in the range of the parameter space. In this study, we detail a non-destructive, easy-to-use approach for characterizing the porosity and tensile strength of pharmaceutical tablets.

Tablet capping predictions of model materials using multivariate approach.

The present study demonstrated the prediction of predominant root causes of capping behavior as a function of the powder rheological and the mechanical behavior of Acetaminophen (APAP) and Ibuprofen (IBU). The authors analyzed powder rheological properties for powder blend permeability, pressure drop, and cohesion. The measured deformation properties were compact porosity, internal air pressure, Brinell hardness, and tensile strength. The data were evaluated qualitatively and quantitatively using multivariate techniques, such as principal component analysis (PCA) and principal component regression (PCR) models, respectively, to identify the effect of powder air entrapment efficiency and mechanical behavior on the tablet capping score. The PCA model indicated that pressure drop, cohesion, API amount, and compression pressure correlated positively, whereas permeability, porosity, internal air pressure, Brinell hardness, and tensile strength correlated negatively to the capping potential. APAP and IBU also showed two independent mechanisms as a function of their amount on the capping score at all compression pressures. APAP and IBU followed an exponential and linear relationship, respectively. Furthermore, the dominant powder rheological and deformation behavior affecting the capping score of each material was identified and quantified using two separate PCR models. These models showed that APAP capping was predominantly dependent on its powder properties, while that of IBU was predominantly based on its deformation properties. In conclusion, APAP and IBU compacts capping had respective air induced and deformation induced capping behavior. The proposed approach can aid in understanding the underlying mechanisms of capping and developing an effective, optimized strategy to ensure tablet quality.

Development of an amorphous nanosuspension by sonoprecipitation-formulation and process optimization using design of experiment methodology.

A Design of Experiment (DoE) methodology was adopted to investigate and optimize process parameters and formulations variables for preparing an amorphous clotrimazole (CLT) nanosuspension by sonoprecipitation technique. The amorphous nanosuspension can provide a synergistic effect of increase in dissolution velocity and kinetic solubility which can be advantageously used to improve bioavailability of low-solubility drugs. A Box-Behnken design was utilized to study the effect of formulation parameters (drug concentration, polymer concentration, and surfactant concentration) and process parameter (antisolvent: solvent ratio) on particle size, polydispersibility index (PDI), and zeta potential of amorphous CLT nanoparticles. Soluplus® and poloxamer 407 were incorporated in the formulation for steric and electrostatic stabilization respectively. The optimized formulation predicted by the developed model was validated experimentally. The micronized amorphous suspension, micronized crystalline suspension and nanocrystalline suspension were prepared as controls. The optimized amorphous nanosuspension and controls were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and polarized light microscopy (PLM) techniques. Additionally, in-vitro dissolution studies were performed. The drug concentration, polymer concentration and antisolvent:solvent ratio were found to be statistically significant in impacting critical quality attributes (CQAs) of drug product. The model developed for zeta potential was insignificant at a 95% confidence interval. The DSC, XRPD and PLM results confirmed the amorphization of CLT by sonoprecipitation process. The DSC thermogram did not show any characteristic endothermic peak, XRPD diffractogram showed amorphous halo pattern whereas PLM images did not illustrate birefringence for amorphous CLT nanosuspension. The in-vitro drug dissolution studies demonstrated relatively higher drug dissolution for amorphous CLT nanosuspension compared to controls at both the dissolution media (de-ionized water and pH 7.2 buffer). The sonoprecipitation process was successfully used to produce a stable amorphous nanosuspension with notably enhanced dissolution velocity by evaluating and optimizing critical process and formulation parameters.

Evaluation of self-nanoemulsifying drug delivery systems using multivariate methods to optimize permeability of captopril oral films.

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.

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.

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.

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.

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.