Critical Formulation Parameters Research Articles

Investigation of Formulation and Process Parameters of Wet Media Milling to Develop Etodolac Nanosuspensions.

Etodolac (ETD) is one of the non-steroidal anti-inflammatory drugs which has low aqueous solubility issues. The objective of this study was to develop ETD nanosuspensions to improve its poor aqueous solubility properties while investigating formulation and process parameters of wet media milling method via design of experiment (DoE) approach. The critical formulation parameters (CFP) were selected as ETD amount, stabilizer type and ratio as well as critical process parameters (CPP) which were bead size, milling time and milling speed. The two-factorial-23 and The Box-Benkhen Designs were generated to evaluate CFP and CPP, respectively. Particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were analyzed as dependent variables. Characterization, physical stability and solubility studies were performed. Optimum nanosuspensions stabilized by PVP K30 and Poloxamer 188 showed 188.5 ± 1.6 and 279.3 ± 6.1nm of PS, 0.161 ± 0.049 and 0.345 ± 0.007 PDI, 14.8 ± 0.3 and 16.5 ± 0.4mV of ZP values, respectively. The thermal properties of ETD did not change after milling and lyophilization process regarding to DSC analysis. Also, the crystalline state of ETD was preserved. The morphology of particle was smooth and spherical on SEM. The dry-nanosuspensions stayed physically stable for six months at room temperature. The solubility of nanosuspensions increased up to 13.0-fold in comparison with micronized ETD. In conclusion, it is found that the poor solubility issue of ETD can be solved by nanosuspension. DoE approach provided benefits such as reducing number of experiments, saving time and improving final product quality by using wet media milling.

Quality by design approach for the preparation of fat-soluble vitamins lipid injectable emulsion.

The fat-soluble vitamins lipid injectable emulsion, a parenteral supplement, commonly used for hospitalized patients to meet daily requirements of fat-soluble vitamins. This study attempts to reduce risk, improve the stability and safety of fat-soluble vitamins lipid injectable emulsion using a Quality by Design (QbD) approach. The quality target product profile and critical quality attributes were defined based on a comprehensive understanding of fat-soluble vitamins lipid injectable emulsions. The emulsions were prepared using a high-pressure homogenization method. Critical quality attributes (CQAs) were identified using risk assessment tools such as fishbone diagram and risk estimation matrix. The assay, mean droplet size, polydispersity index, zeta potential, and the volume-weighted percentage of fat greater than 5 μm (PFAT5) were identified as CQAs. Accordingly, three critical formulation and process parameters for the emulsions were the percentage of emulsifier, homogenization pressure, and homogenization recirculation. The design space was obtained via a design of experiment (DoE), and an optimum formulation was successfully prepared. All physicochemical attributes of the optimal formulation were within the design space (i.e., droplet size: 217.2 ± 0.37 nm; polydispersity index: 0.115 ± 0.012; PFAT5: less than 0.05%; zeta potential: -34.6 ± 1.09 mV; and viscosity: 20.95 mPa at 0.1 s-1). The optimal formulation remained acceptable physicochemical stability at 25 ± 2 °C/60% RH ± 5% RH over a 12-month period. Safety of the optimal emulsion was evaluated as acceptable through the determination of lysophospholipid content and an in vitro hemolysis assay. In conclusion, an optimal lipid injectable emulsion for fat-soluble vitamins was successfully prepared using a QbD approach.

Development of Paclitaxel and Flurbiprofen Co-Loaded PLGA Nanoparticles: Understanding Critical Formulation and Process Parameters Using Plackett–Burman Design

DOI : 10.26650/IstanbulJPharm.2019.19036 Nano drug co-delivery system is a popular strategy for combined application of two or more anticancer and/or synergistic drugs. Synergistic effects of nonsteroidal anti-inflammatory drugs and anti-cancer drugs in cancer treatment are shown in the literature. In this study, it was aimed to screen and understand critical formulation and process parameters inthe preparationflurbiprofen and paclitaxel co-loaded nanoparticles for developing an anti-cancer nano co-delivery system. With this aim, critical parameters were determined using Plackett–Burman experimental design (DoE). Flurbiprofen and paclitaxel drug loading amounts were considered as critical quality attributes to controleffective drug loading ratio. Furthermore, average particle size and zeta potential were also defined as critical quality attributes in order to optimize passive drug targeting and colloidal stability. Surfactant type was determined as the most significant factors for the average particle size and zeta potential. For flurbiprofen and paclitaxel drug loading into the nanoparticles, amounts of both flurbiprofen and paclitaxel were determined as critical factors. Consequently, paclitaxel and flurbiprofen were efficiently loaded into nanoparticles and the impact of the formulation variables were successfully screened by a DoE. By controlling the determined parameters, therapeutic efficacy of co-loaded drug nanoparticles could be maximized in further studies. You may cite this article as : Sahin A, Caban-Toktas S, Tonbul H, Yerlikaya F, Aktas Y, Capan Y (2019). Development of Paclitaxel and Flurbiprofen Co-Loaded PLGA Nanoparticles: Understanding Critical Formulation and Process Parameters Using Plackett–Burman Design. Istanbul J Pharm 10.26650/IstanbulJPharm.2019.19036.

Formulation Optimization of Polyox Based Modified Release Drug Delivery System

Polyethylene Oxide (PEOs) offer specific advantages to be used in pharmaceutical products as release modifiers by forming a hydrogel around the dosage form in aqueous environment causing the drug to follow a diffusional path before releasing into the media. The strength of the hydrogel governs the release retardation capacity of the PEO system. The objective of this dissertation work was to use the Design of Experiments methodology to develop and optimize a PEO based modified release formulation of a highly water-soluble drug like Metoprolol succinate. The effect of the different viscosity grade PEOs, their concentration with respect to the drug, combination of two different viscosity grades, % drug content in the formulation and the use of water soluble / insoluble fillers on the dissolution of metoprolol succinate was studied. The critical formulation parameters namely PEO concentration and % drug content were chosen as input factors and dissolution at 1, 4, 8 and 20 hours was recorded as responses to carry out optimization using the DOE approach. The results obtained after statistical treatment of data provided a design space that can be used for achieving the desired formulation profile. The model has been validated to predict the effect of the input factors (PEO type and concentration and % drug content) on the responses (in vitro dissolution).
 Keywords: Polyethylene Oxide, Modified Release Drug Delivery System, Metoprolol

Identification of Factors of Importance for Spray Drying of Small Interfering RNA-Loaded Lipidoid-Polymer Hybrid Nanoparticles for Inhalation.

With the recent approval of the first small interfering RNA (siRNA) therapeutic formulated as nanoparticles, there is increased incentive for establishing the factors of importance for the design of stable solid dosage forms of such complex nanomedicines. The aims of this study were: (i) to identify factors of importance for the design of spray-dried siRNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles (LPNs), and (ii) to evaluate their influence on the resulting powders by using a quality-by-design approach. Critical formulation and process parameters were linked to critical quality attributes (CQAs) using design of experiments, and an optimal operating space (OOS) was identified. A series of CQAs were identified based on the quality target product profile. The loading (ratio of LPNs to the total solid content) and the feedstock concentration were determined as critical parameters, which were optimized systematically. Mannitol was chosen as stabilizing excipient due to the low water content of the resulting powders. The loading negatively affected the colloidal stability of the LPNs, whereas feedstock concentration correlated positively with the powder particle size. The optimal mannitol-based solid formulation, defined from the OOS, displayed a loading of 5% (w/w), mass median aerodynamic diameter of 3.3 ± 0.2μm, yield of 60.6 ± 6.6%, and a size ratio of 1.15 ± 0.03. Dispersed micro-embedded LPNs had preserved physicochemical characteristics as well as in vitro siRNA release profile and gene silencing, as compared to non-spray-dried LPNs. The optimal solid dosage forms represent robust formulations suitable for higher scale-up manufacturing.

Comparison and process optimization of PLGA, chitosan and silica nanoparticles for potential oral vaccine delivery.

Aim: The study compared performance of nanoparticles prepared from synthetic organic, natural organic and inorganic materials as vaccine delivery platforms. Materials& methods: Various formulation (concentration, polymer/silica:surfactant ratio, solvent) and process parameters (homogenization speed and time, ultrasonication) affecting functional performance characteristics of poly(lactic-co-glycolic acid) (PLGA), chitosan and silica-based nanoparticles containing bovine serum albumin were investigated. Nanoparticles were characterized using dynamic light scattering, x-ray diffraction, scanning/transmission electron microscopy, Fourier transform infrared spectroscopy and in vitro protein release. Results: Critical formulation parameters were surfactant concentration (PLGA, silica) and polymer concentration (chitosan). Optimized nanoparticles were spherical in shape with narrow size distribution and size ranges of 100-300nm (blank) and 150-400nm (protein loaded). Protein encapsulation efficiency was 26-75% and released within 48 h in a sustained manner. Conclusion: Critical formulation and process parameters affected size of PLGA, chitosan and silica nanoparticles and protein encapsulation, while silica produced the smallest and most stable nanoparticles.

Melatonin loaded lipid enriched chitosan microspheres – Hybrid dressing for moderate exuding wounds

The aim of this study was to develop nanostructured lipid carrier (NLC)-loaded chitosan-based microspheres as innovative dry powder wound dressing, with melatonin incorporated in both, NLC and chitosan matrix of the proposed hybrid system. Melatonin-loaded NLCs were prepared by a hot homogenization technique, while NLC-loaded microspheres were produced by a spray-drying method. To optimize the critical formulation and process parameters for both NLC and hybrid system, a definitive screening design was employed. NLC particle size, hybrid system production yield, particle size, moisture content, and zeta potential were investigated as responses. The optimized hybrid system was characterized by prolonged melatonin release, good flowability and appropriate extent of fluid uptake. In contact with simulated wound fluid, the hybrid system swelled, turning into a hydrogel layer. The presence of lipid nanoparticles attenuated the evaporative water loss showing the potential to provide optimal hydration for moderate exuding wounds. The hybrid system was proven to be biocompatible with skin keratinocytes and fibroblasts and moreover, showed antimicrobial activity against Staphylococcus aureus and S. aureus MRSA strain.

Comprehensive quality by design approach for stable nanocrystalline drug products

The novelty of the present research is application of a comprehensive quality by design (QbD) approach to minimize errors in product optimization and validation for the development of a stable nanocrystalline zileuton (BCS class II drug) formulation. A QbD approach was used to identify, optimize and validate the critical processes parameters (wet media milling and spray drying) and critical formulation parameters (drug and excipient concentrations). The milling time, milling speed, inlet temperature, aspirator rate, feed flow rate and drug concentration had a significant influence on the particle size and total product yield of the nanocrystalline zileuton. Trehalose compared to mannitol was determined to be a better stabilizer during spray drying processing. Stability studies revealed the following trend after 12 months: 4 °C (most stable) >25 °C/60% RH > 40 °C/75% RH (least stable) for the optimized spray-dried nanocrystalline zileuton in terms of physicochemical attributes, crystallinity and in vitro dissolution testing. Based on the comprehensive QbD approach, stable spray-dried nanocrystalline zileuton was obtained with exceptionally high total product yield (∼80% w/w) and small particle size (276.4 ± 27.54 nm) with low PDI (0.109 ± 0.056 units). Drug release from the formulations followed a particle size dependent dissolution trend. Additionally, pH switch dissolution testing indicated that complete drug release from the nanoformulations was observed at intestinal pH (pH 6.8) within 1–2 h of the shift from the stomach pH (pH 1.2).

Nanoamorphous drug products – Design and development

Most of the recent drug compounds coming out of the drug discovery pipeline are labile (multiple polymorphs), and need to be developed into robust marketed oral drug formulations. There are only 22 oral macroamorphous drug products approved by FDA and till date none approved oral nanoamorphous drug products. However, there are several oral nanoamorphous drug formulations (including both labile and non-labile drugs) being researched and a few of these are in the clinical trials. Due to the labile nature of these drug compounds, there is a need to utilize a controlled strategy for design and development of robust nanoamorphous drug formulations in order to prevent any physicochemical instability. The present research focuses on the use of a novel integrated critical process parameters and critical formulation parameters (iCPP-CFPs) DoE approach for the design and development of stable nanoamorphous spironolactone (BCS class II compound with eight polymorphic forms). There are possibilities of the interconversion of these polymorphic forms during processing (manufacturing nanoamorphous particles) and during storage. In the present study, polymorphic transitions (amorphous to crystalline and anhydrous to hydrate) were carefully monitored via orthogonal solid-state characterization tools. Significant polymorphic transitions were observed in the formulations stored at 40 °C/75% RH over six months, however the formulations stored at 4 °C were stable. The significant iCPP-CFPs (solvent-to-antisolvent ratio, drug concentration and inlet temperature of the spray dryer) were critically investigated for their influence on different CQAs (critical quality attributes). Solvent-to-antisolvent ratio and inlet temperature were identified to be the significant iCPP-CFPs. Particle size and total product yield were identified to be the significant CQAs. Lab-scale manufacturing of the spray dried nanoamorphous spironolactone resulted in a remarkably high total product yield (82.4 ± 3.91% w/w) with a uniform and homogenous particle size (244.2 ± 23.32 nm). Furthermore, the physicochemical attributes and the drug release criteria of the nanoamorphous spironolactone were compared with two marketed products (spironolactone tablets, USP 100 mg (Pfizer and Mylan)) and other in-house formulations. In addition, nanoamorphous spironolactone showed a significantly superior kinetic solubility/dissolution rate (10-fold) with a longer supersaturation time (∼6h) compared to the in-house formulations.

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.

Development of PLGA nanoparticle loaded dissolving microneedles and comparison with hollow microneedles in intradermal vaccine delivery

Skin is an attractive but also very challenging immunisation site for particulate subunit vaccines. The aim of this study was to develop hyaluronan (HA)-based dissolving microneedles (MNs) loaded with PLGA nanoparticles (NPs) co-encapsulating ovalbumin (OVA) and poly(I:C) for intradermal immunisation. The NP:HA ratio used for the preparation of dissolving MNs appeared to be critical for the quality of MNs and their dissolution in ex vivo human skin. Asymmetrical flow field-flow fractionation and dynamic light scattering were used to analyse the NPs released from the MNs in vitro. Successful release of the NPs depended on the drying conditions during MN preparation. The delivered antigen dose from dissolving MNs in mice was determined to be 1 µg OVA, in NPs or as free antigen, by using near-infrared fluorescence imaging. Finally, the immunogenicity of the NPs after administration of dissolving MNs (NP:HA weight ratio 1:4) was compared with that of hollow MN-delivered NPs in mice. Immunization with free antigen in dissolving MNs resulted in equally strong immune responses compared to delivery by hollow MNs. However, humoral and cellular immune responses evoked by NP-loaded dissolving MNs were inferior to those elicited by NPs delivered through a hollow MN. In conclusion, we identified several critical formulation parameters for the further development of NP-loaded dissolving MNs.

DEVELOPMENT AND EVALUATION OF MODIFIED RELEASE MATRIX TABLETS OF MILNACIPRAN HCL USING MELT GRANULATION TECHNIQUE

The objective of the present study was to identify critical formulation parameters affecting the drug release from modified release wax matrix tablet of milnacipran hydrochloride employing the concept of design of experiments.The optimized amount of Compritol 888 ATO(intragranular) (X1), lactose (X2) and Compritol 888ATO (extragranular)(X3) were determined employing simplex latticedesign. The tablets were prepared using melt granulation technique. The in vitro drug release study was carried out in an acidic medium (pH 1.2) for 2 h and thereafter the dissolution study was conducted in phosphate buffer (pH 6.8).The selected dependent variables were the cumulative percentage of milnacipran hydrochloride dissolved at 1 (Y1), 8 (Y8), 16 (Y16) and 24 h (Y24). Mathematical models, correlating the independent variables with dependent variables were evolved. Optimization was performed for the three independent variables using the stated target ranges; Y1≤20%; Y8=45±5%; Y16=72±5%; Y24=100%. The optimized amounts of Compritol ATO888 (intragranular)(X1), lactose (X2) and Compritol 888ATO (extragranular)(X3), were found to be 60, 55 and 30 mg, respectively.The optimized formulation showed a release profile that was close to the predicted values. The drug was released by anomalous diffusion from the optimized formulation. Compritol 888ATO (intragranular) (X1), lactose (X2) and Compritol 888ATO(extragranular) (X3) were identified as critical variables.

Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling

The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating

Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher Cmax), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.

Engineering of budesonide-loaded lipid-polymer hybrid nanoparticles using a quality-by-design approach

Chronic obstructive pulmonary disease (COPD) is a complex disease, characterized by persistent airflow limitation and chronic inflammation. The purpose of this study was to design lipid-polymer hybrid nanoparticles (LPNs) loaded with the corticosteroid, budesonide, which could potentially be combined with small interfering RNA (siRNA) for COPD management. Here, we prepared LPNs based on the biodegradable polymer poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid dioleyltrimethylammonium propane (DOTAP) using a double emulsion solvent evaporation method. A quality-by-design (QbD) approach was adopted to define the optimal formulation parameters. The quality target product profile (QTPP) of the LPNs was identified based on risk assessment. Two critical formulation parameters (CFPs) were identified, including the theoretical budesonide loading and the theoretical DOTAP loading. The CFPs were linked to critical quality attributes (CQAs), which included the intensity-based hydrodynamic particle diameter (z-average), the polydispersity index (PDI), the zeta-potential, the budesonide encapsulation efficiency, the actual budesonide loading and the DOTAP encapsulation efficiency. A response surface methodology (RSM) was applied for the experimental design to evaluate the influence of the CFPs on the CQAs, and to identify the optimal operation space (OOS). All nanoparticle dispersions displayed monodisperse size distributions (PDI<0.2) with z-averages of approximately 150nm, suggesting that the size is not dependent on the investigated CFPs. In contrast, the zeta-potential was highly dependent on the theoretical DOTAP loading. Upon increased DOTAP loading, the zeta-potential reached a maximal point, after which it remained stable at the maximum value. This suggests that the LPN surface is covered by DOTAP, and that the DOTAP loading is saturable. The actual budesonide loading of the LPNs was mainly dependent on the initial amount of budesonide, and a clear positive effect was observed, which shows that the interaction between drug and PLGA increases when increasing the initial amount of budesonide. The OOS was modeled by applying the QTPP. The OOS had a budesonide encapsulation efficiency higher than 30%, a budesonide loading above 15μg budesonide/mg PLGA, a zeta-potential higher than 35mV and a DOTAP encapsulation efficiency above 50%. This study shows the importance of systematic formulation design for understanding the effect of formulation parameters on the characteristics of LPNs, eventually resulting in the identification of an OOS.

Spray drying ternary amorphous solid dispersions of ibuprofen – An investigation into critical formulation and processing parameters

A design of experiment (DoE) approach was used to investigate the critical formulation and processing parameters in spray drying ternary amorphous solid dispersions (ASDs) of ibuprofen. A range of 16 formulations of ibuprofen, HPMCP-HP55 and Kollidon VA 64 were spray dried. Statistical analysis revealed the interrelation of various spray drying process conditions and formulation factors, namely solution feed rate, inlet temperature, Active Pharmaceutical Ingredient (API)/excipients ratio and dichloromethane (DCM)/methanol (MeOH) ratio. Powder X-ray diffraction analysis (PXRD) showed that all the samples with the lowest API/excipient ratio (1:4) were amorphous, while others were crystalline. Moreover, differential scanning calorimetry (DSC) analysis was employed to investigate ASD formulation more in-depth. The glass transition temperatures (Tg) of all ASDs were in the range 70–79°C, while crystalline formulations displayed an endothermic peak of melting of crystalline ibuprofen in the range of 50–80°C. The high Tg of ASDs was an indication of highly stable ASD formulations as verified via PXRD at zero day and afterward at 1, 1.5, 3 and 6month intervals. The intermolecular interactions between ibuprofen molecule and excipients were studied by Fourier transform infrared spectroscopy (FTIR) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. FTIR and Carbon-13 ssNMR analysis indicated that hydrogen bond formation involving the carboxyl group in ibuprofen within the ASDs is likely. More importantly, the solubility of ibuprofen in ASD formulations is improved compared to pure ibuprofen. This was due to both the amorphous structure of ibuprofen and of the existence of amphiphilic excipient, Kollidon VA 64, in the formulation.

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization

Objective: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.Methods: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.Results: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product’s disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load).Conclusions: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.

Formulation of dried lignans nanosuspension with high redispersibility to enhance stability, dissolution, and oral bioavailability

Herpetospermum caudigerum lignans (HTL), one of the potential drugs with anti-hepatitis B virus and hepatoprotective effects, has limited clinical applications because of poor aqueous solubility and low bioavailability. Both herpetrione (HPE) and herpetin (HPN) are the most abundant ingredients in HTL and exhibit weak acidity. The purpose of the present study was to produce dried preparations of HTL (composed of HPE and HPN) nanosuspensions (HTL-NS) with high redispersibility using lyophilization technology. The HTL-NS was prepared by utilizing precipitation-combined homogenization technology based on acid-base neutralization reactions, and critical formulation and process parameters affecting the characteristics of HTL-NS were optimized. The resultant products were characterized by particle size analysis, SEM, XRD, stability, solubility, dissolution and in vivo bioavailability. HTL-NS showed near-spherical-shaped morphology and the size was 243 nm with a narrow PDI value of 0.187. The dried preparations with a relatively large particle size of 286 nm and a PDI of 0.215 were achieved by using 4% (W/V) mannitol as cryoprotectants, and had a better stability at 4 or 25 °C for 2 months, compared to HTL-NS. In the in vitro test, the dried preparations showed markedly increased solubility and dissolution velocity. Besides, in the in vivo evaluation, it exhibited significant increases in AUC0–t, Cmax,MRT and a decrease in Tmax, compared to the raw drug. In conclusion, our results provide a basis for the development of a drug delivery system for poorly water-soluble ingredients with pH-dependent solubility.

Risk management and statistical multivariate analysis approach for design and optimization of satranidazole nanoparticles

Rapidly evolving technical and regulatory landscapes of the pharmaceutical product development necessitates risk management with application of multivariate analysis using Process Analytical Technology (PAT) and Quality by Design (QbD). Poorly soluble, high dose drug, Satranidazole was optimally nanoprecipitated (SAT-NP) employing principles of Formulation by Design (FbD). The potential risk factors influencing the critical quality attributes (CQA) of SAT-NP were identified using Ishikawa diagram. Plackett-Burman screening design was adopted to screen the eight critical formulation and process parameters influencing the mean particle size, zeta potential and dissolution efficiency at 30min in pH7.4 dissolution medium. Pareto charts (individual and cumulative) revealed three most critical factors influencing CQA of SAT-NP viz. aqueous stabilizer (Polyvinyl alcohol), release modifier (Eudragit® S 100) and volume of aqueous phase. The levels of these three critical formulation attributes were optimized by FbD within established design space to minimize mean particle size, poly dispersity index, and maximize encapsulation efficiency of SAT-NP. Lenth's and Bayesian analysis along with mathematical modeling of results allowed identification and quantification of critical formulation attributes significantly active on the selected CQAs. The optimized SAT-NP exhibited mean particle size; 216nm, polydispersity index; 0.250, zeta potential; −3.75mV and encapsulation efficiency; 78.3%. The product was lyophilized using mannitol to form readily redispersible powder. X-ray diffraction analysis confirmed the conversion of crystalline SAT to amorphous form. In vitro release of SAT-NP in gradually pH changing media showed <20% release in pH1.2 and pH6.8 in 5h, while, complete release (>95%) in pH7.4 in next 3h, indicative of burst release after a lag time. This investigation demonstrated effective application of risk management and QbD tools in developing site-specific release SAT-NP by nanoprecipitation.

Preparation of ritonavir nanosuspensions by microfluidization using polymeric stabilizers: I. A Design of Experiment approach

The objective of this study was to prepare ritonavir (RTV) nanosuspensions, an anti-HIV protease inhibitor, to solve its poor water solubility issues. The microfluidization method with a pre-treatment step was used to obtain the nanosuspensions. Design of Experiment (DoE) approach was performed in order to understand the effect of the critical formulation parameters which were selected as polymer type (HPMC or PVP), RTV to polymer ratio, and number of passes. Interactions between the formulation variables were evaluated according to Univariate ANOVA. Particle size, particle size distribution and zeta potential were selected as dependent variables. Scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry were performed for the in vitro characterization after lyophilization of the optimum nanosuspension formulation. The saturation solubility was examined in comparison with coarse powder, physical mixture and nanosuspension. In vitro dissolution studies were conducted using polyoxyethylene 10 lauryl ether (POE10LE) and biorelevant media (FaSSIF and FeSSIF). The results showed nanosuspensions were partially amorphous and spherically shaped with particle sizes ranging from 400 to 600nm. Moreover, 0.1–0.4 particle size distribution and about −20mV zeta potential values were obtained. The nanosuspension showed a significantly increased solubility when compared to coarse powder (3.5 fold). Coarse powder, physical mixture, nanosuspension and commercial product dissolved completely in POE10LE; however, cumulative dissolved values reached ~20% in FaSSIF for the commercial product and nanosuspension. The nanosuspension showed more than 90% drug dissolved in FeSSIF compared to the commercial product which showed ~50% in the same medium. It was determined that RTV dissolution was increased by nanosuspension formulation. We concluded that DoE approach is useful to develop nanosuspension formulation to improve solubility and dissolution rate of RTV.