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.

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.

Hybridized nanoamorphous micellar dispersion using a QbD-DM3 linked rational product design strategy for ritonavir: A BCS IV drug.

A QbD-DM3 linked rational product design strategy was adopted to create a hybridized ritonavir (RTV, BCS Class IV) nanoamorphous micellar dispersion (RTV-NAD). A DM3 research strategy was employed in conjunction with the quality-by-design spaces, and quality target product profile to link the critical material attributes and critical process parameters to the quality target product profile's critical product attributes QbD elements. A Box-Behnken design and multivariate analysis using multiple linear regression and partial least squares provided data analysis. The hybridized strategy leveraged three different mechanisms to increase RTV's solubility and four mechanisms to increase its dissolution rate. Statistically significant models were generated for critical product attributes: particle size (p = 0.0000, R2 adjusted = 0.9513), polydispersity index (p = 0.0002, R2 adjusted = 0.6398), zeta potential (p = 0.0000, R2 adjusted = 0.9744), and drug loading on a dry basis (p = 0.0000, R2 adjusted = 0.9951). The impact of drug concentration, Soluplus® concentration, and solvent:antisolvent ratio, their interactions and square effects on the critical product attributes were assessed by multivariate analysis. The QbD optimal formulation was determined for RTV-NAD. Multiple linear regression and partial least squares computational predictability was evaluated using three verification batches. The prediction error for critical product attributes was <5%. RTV-NAD and ritonavir microsuspension were characterized by x-ray diffraction and in-vitro dissolution studies. X-ray diffraction confirmed the amorphous nature of the RTV-NAD. RTV-NAD exhibited a 'spring-hover' dissolution profile at pH 4.5. At pH 6.8, a classic 'spring-parachute' dissolution behavior was observed.

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.

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.

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.

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.