Investigation of Polymer-Surfactant and Polymer-Drug-Surfactant Miscibility for Solid Dispersion

In a solid dispersion (SD), the drug is generally dispersed either molecularly or in the amorphous state in polymeric carriers, and the addition of a surfactant is often important to ensure drug release from such a system. The objective of this investigation was to screen systematically polymer-surfactant and polymer-drug-surfactant miscibility by using the film casting method. Miscibility of the crystalline solid surfactant, poloxamer 188, with two commonly used amorphous polymeric carriers, Soluplus® and HPMCAS, was first studied. Then, polymer-drug-surfactant miscibility was determined using itraconazole as the model drug, and ternary phase diagrams were constructed. The casted films were examined by DSC, PXRD and polarized light microscopy for any crystallization or phase separation of surfactant, drug or both in freshly prepared films and after exposure to 40°C/75% RH for 7, 14, and 30 days. The miscibility of poloxamer 188 with Soluplus® was <10% w/w, while its miscibility with HPMCAS was at least 30% w/w. Although itraconazole by itself was miscible with Soluplus® up to 40% w/w, the presence of poloxamer drastically reduced its miscibility to <10%. In contrast, poloxamer 188 had minimal impact on HPMCAS-itraconazole miscibility. For example, the phase diagram showed amorphous miscibility of HPMCAS, itraconazole, and poloxamer 188 at 54, 23, and 23% w/w, respectively, even after exposure to 40°C/75% RH for 1 month. Thus, a relatively simple and practical method of screening miscibility of different components and ultimately physical stability of SD is provided. The results also identify the HPMCAS-poloxamer 188 mixture as an optimal surface-active carrier system for SD.     

De Novo Approach to Utilize Mango (<Emphasis Type="Italic">Mangifera indica</Emphasis> L.) Seed Kernel Lipid in Pharmaceutical Lipid Nanoformulation

The naturally occurring lipids are non-toxic and biocompatible, hence suitable for pharmaceutical applications. The present study reports the application of mango lipid as a safe pharmaceutical excipient in the formulation of nanostructured lipid carriers (NLCs). The mango lipid was extracted by hot continuous percolation process using a Soxhlet apparatus and analyzed as per USP requirements by TLC and LC-MS. The safety profile of the lipid was studied by acute toxicity study in a rat model as per OECD guidelines. NLC formulation was developed with the physically modified mango lipid as the solid lipid and oleic acid as the liquid lipid by the modified emulsification technique. The compatibility of the lipid with other excipients was studied by differential scanning calorimetry (DSC) and FT-IR analysis. Cytotoxicity of the NLC formulation was studied with mouse brain endothelial cells (bEnd.3) by MTT assay. The TLC and LC-MS studies suggest that the mango lipid contains fatty acids composed of oleic acid (43.8% w/w), linoleic acid (3.6% w/w), stearic acid (43.2% w/w), palmitic acid (4.9% w/w), linolenic acid (2.3% w/w), and arachidic acid (2.2% w/w). The acute toxicity study and MTT assay suggest the safe use of the mango lipid at the cellular level in the living system. The spherical homogeneous nanometric NLCs were developed. DSC and FT-IR study confirm the compatibility of the lipid with the general components of the lipid nanoparticles. This work provides a new dimension to Mangifera indica L. lipid for its safe use in the development of novel lipid nanoformulations for drug delivery.     

Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil® HFA (albuterol sulfate suspension) and Qvar® (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D₅₀, 1.4 to 2.5 μm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D₅₀) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters.     

Porous Silica-Supported Solid Lipid Particles for Enhanced Solubilization of Poorly Soluble Drugs

Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.     

Optimization of Weight Ratio for DSPE-PEG/TPGS Hybrid Micelles to Improve Drug Retention and Tumor Penetration

Purpose

To enhance therapeutic efficacy and prevent phlebitis caused by Asulacrine (ASL) precipitation post intravenous injection, ASL-loaded hybrid micelles with size below 40 nm were developed to improve drug retention and tumor penetration.

Methods

ASL-micelles were prepared using different weight ratios of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethyleneglycol-2000 (DSPE-PEG₂₀₀₀) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymers. Stability of micelles was optimized in terms of critical micelle concentration (CMC) and drug release properties. The encapsulation efficiency (EE) and drug loading were determined using an established dialysis-mathematic fitting method. Multicellular spheroids (MCTS) penetration and cytotoxicity were investigated on MCF-7 cell line. Pharmacokinetics of ASL-micelles was evaluated in rats with ASL-solution as control.

Results

The ASL-micelles prepared with DSPE-PEG₂₀₀₀ and TPGS (1:1, w/w) exhibited small size (~18.5 nm), higher EE (~94.12%), better sustained in vitro drug release with lower CMC which may be ascribed to the interaction between drug and carriers. Compared to free ASL, ASL-micelles showed better MCTS penetration capacity and more potent cytotoxicity. Pharmacokinetic studies demonstrated that the half-life and AUC values of ASL-micelles were approximately 1.37-fold and 3.49-fold greater than that of free ASL.

Conclusions

The optimized DSPE-PEG₂₀₀₀/TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.

     

Development of a Flow-Through USP-4 Apparatus Drug Release Assay to Evaluate Doxorubicin Liposomes

Doxil® is a complex parenteral doxorubicin (DOX) liposome formulation approved by the FDA. For generic doxorubicin liposomes, analyzing the release profile of DOX is important for quality control and comparability studies. However, there is no robust standard drug release assay available for doxorubicin liposomes. In this study, we describe a USP-4 apparatus assay capable of discriminating DOX liposomal formulations based on release profile. Establishment of the assay was hindered by limited DOX release from liposomes in physiological conditions at 37°C. The addition of NH₄HCO₃ to the release media facilitated DOX release proportionally to the salt concentration added but caused precipitation of released drug in USP-4 apparatus. Precipitation of DOX was avoided by adding hydroxypropyl-cyclodextrin (HP-CD) to the release medium. We optimized conditions for DOX release by varying a number of parameters such as: concentration of HP-CD, testing temperature, and concentration of tested samples. The optimized release medium contained: 100 mM NH₄HCO₃, 75 mM 2-(N-morpholino) ethanesulfonic acid (MES) and 5% w/v HP-CD, 5% w/v sucrose, 0.02% w/v NaN₃ (pH 6). The drug release assay was performed at 45°C. The optimized release assay can discriminate between DOX liposomal formulations of different compositions, physicochemical properties, and prepared by different manufacturing methods. This indicates that the assay could be used to compare DOX release from generic DOX formulations to the innovator product Doxil®.     

Positive effects of Red Bull® Energy Drink on driving performance during prolonged driving

Background

The purpose of this study was to examine if Red Bull® Energy Drink can counteract sleepiness and driving impairment during prolonged driving.

Methods

Twenty-four healthy volunteers participated in this double-blind placebo-controlled crossover study. After 2 h of highway driving in the STISIM driving simulator, subjects had a 15-min break and consumed Red Bull® Energy Drink (250 ml) or placebo (Red Bull® Energy Drink without the functional ingredients: caffeine, taurine, glucuronolactone, B vitamins (niacin, pantothenic acid, B6, B12), and inositol) before driving for two additional hours. A third condition comprised 4 h of uninterrupted driving. Primary parameter was the standard deviation of lateral position (SDLP), i.e., the weaving of the car. Secondary parameters included SD speed, subjective driving quality, sleepiness, and mental effort to perform the test.

Results

No significant differences were observed during the first 2 h of driving. Red Bull® Energy Drink significantly improved driving relative to placebo: SDLP was significantly reduced during the 3rd (p?p?p?p?p?p?p?

Conclusion

Red Bull® Energy Drink significantly improves driving performance and reduces driver sleepiness during prolonged highway driving.

     

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P _eff,int ) to predict the regional gastrointestinal (GI) absorption (f _abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin’s modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F _G ) rather than due to a higher colonic f _abs , thus confirming previous hypotheses. The predicted f _abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F _G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F _G as the main factor responsible for the higher bioavailability of oxybutynin’s OROS® formulation vs. the IR.     

A new <Emphasis Type="BoldItalic">in vitro</Emphasis> lipid digestion – <Emphasis Type="BoldItalic">in vivo</Emphasis> absorption model to evaluate the mechanisms of drug absorption from lipid-based formulations

Purpose

In vitro lipid digestion models are commonly used to screen lipid-based formulations (LBF), but in vitro-in vivo correlations are in some cases unsuccessful. Here we enhance the scope of the lipid digestion test by incorporating an absorption ‘sink’ into the experimental model.

Methods

An in vitro model of lipid digestion was coupled directly to a single pass in situ intestinal perfusion experiment in an anaesthetised rat. The model allowed simultaneous real-time analysis of the digestion and absorption of LBFs of fenofibrate and was employed to evaluate the influence of formulation digestion, supersaturation and precipitation on drug absorption.

Results

Formulations containing higher quantities of co-solvent and surfactant resulted in higher supersaturation and more rapid drug precipitation in vitro when compared to those containing higher quantities of lipid. In contrast, when the same formulations were examined using the coupled in vitro lipid digestion – in vivo absorption model, drug flux into the mesenteric vein was similar regardless of in vitro formulation performance.

Conclusion

For some drugs, simple in vitro lipid digestion models may underestimate the potential for absorption from LBFs. Consistent with recent in vivo studies, drug absorption for rapidly absorbed drugs such as fenofibrate may occur even when drug precipitation is apparent during in vitro digestion.

     

Biodegradable Nanoparticles Improve Oral Bioavailability of Amphotericin B and Show Reduced Nephrotoxicity Compared to Intravenous Fungizone®

Purpose

Amphotericin B (AMB), an effective antifungal and antileishmanial agent associated with low oral bioavailability (0.3%) and severe nephrotoxicity, was entrapped into poly(lactide-co-glycolide) (PLGA) nanoparticles to improve the oral bioavailability and to minimize the adverse effects associated with it.

Materials and Methods

The AMB-nanoparticles (AMB-NP) were prepared by nanoprecipitation method employing Vitamin E-TPGS as a stabilizer. In vitro release was carried out using membrane dialysis method. The in vitro hemolytic activity of AMB-NP was evaluated by incubation with red blood cells (RBCs). The acute nephrotoxicity profile and oral bioavailability of AMB-NP were evaluated in rats.

Results

The prepared AMB-NP formulation contained monodispersed particles in the size range of 165.6?±?2.9 nm with 34.5?±?2.1% entrapment at 10% w/w initial drug loading. AMB-NP formulation showed biphasic drug release, an initial rapid release followed by a sustained release. The AMB-NP formulation exerted lower hemolysis and nephrotoxicity as compared to Fungizone®. The relative oral bioavailability of the AMB-NP was found to be ～800% as compared to Fungizone®.

Conclusion

Together, these results offer a possibility of treating systemic fungal infection and leishmaniasis with oral AMB-NP, which could revolutionize the infectious disease treatment modalities.

     

Lipid-based Formulations for Danazol Containing a Digestible Surfactant,Labrafil M2125CS: <Emphasis Type="BoldItalic">In Vivo</Emphasis> Bioavailability and Dynamic <Emphasis Type="BoldItalic">In Vitro</Emphasis> Lipolysis

Purpose

To evaluate the use of Labrafil® M2125CS as a lipid vehicle for danazol. Further, the possibility of predicting the in vivo behavior with a dynamic in vitro lipolysis model was evaluated.

Methods

Danazol (28 mg/kg) was administered orally to rats in four formulations: an aqueous suspension, two suspensions in Labrafil® M2125CS (1 and 2 ml/kg) and a solution in Labrafil® M2125CS (4 ml/kg).

Results

The obtained absolute bioavailabilities of danazol were 1.5?±?0.8%; 7.1?±?0.6%; 13.6?±?1.4% and 13.3?±?3.4% for the aqueous suspension, 1, 2 and 4 ml Labrafil® M2125CS per kg respectively. Thus administration of danazol with Labrafil® M2125CS resulted in up to a ninefold increase in the bioavailability, and the bioavailability was dependent on the Labrafil® M2125CS dose. In vitro lipolysis of the formulations was able to predict the rank order of the bioavailability from the formulations, but not the absorption profile of the in vivo study.

Conclusions

The bioavailability of danazol increased when Labrafil® M2125CS was used as a vehicle, both when danazol was suspended and solubilized in the vehicle. The dynamic in vitro lipolysis model could be used to rank the bioavailabilities of the in vivo data.

     

The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation

Purpose

Twin screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to continuous granulation of moisture sensitive drugs. However, knowledge of the material behavior during TS HMG is crucial to optimize the formulation, process and resulting granule properties. The aim of this study was to evaluate the agglomeration mechanism during TS HMG using a rheometer in combination with differential scanning calorimetry (DSC).

Methods

An immiscible drug-binder formulation (caffeine-Soluplus^®) was granulated via TS HMG in combination with thermal and rheological analysis (conventional and Rheoscope), granule characterization and Near Infrared chemical imaging (NIR-CI).

Results

A thin binder layer with restricted mobility was formed on the surface of the drug particles during granulation and is covered by a second layer with improved mobility when the Soluplus^® concentration exceeded 15% (w/w). The formation of this second layer was facilitated at elevated granulation temperatures and resulted in smaller and more spherical granules.

Conclusion

The combination of thermal and rheological analysis and NIR-CI images was advantageous to develop in-depth understanding of the agglomeration mechanism during continuous TS HMG and provided insight in the granule properties as function of process temperature and binder concentration.

     

Combination of Oxaliplatin and Vit.E-TPGS in Lipid Nanosystem for Enhanced Therapeutic Efficacy in Colon Cancers

Purpose

The main aim of present study was to prepare the oxaliplatin (OXL)-loaded D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS)-based lipid nanoparticles to enhance the anticancer effect in colon cancer cells.

Methods

The nanoparticles were nanosized and spherical shaped and exhibited controlled release kinetics. Flow cytometer and confocal laser scanning microscopy (CLSM) showed a remarkable uptake of nanoparticles in cancer cells in a time-dependent manner.

Results

The presence of TPGS remarkably increased the anticancer effect of OXL in HT-29 colon cancer cells. The IC50 value of free OXL was 4.25 μg/ml whereas IC50 value of OXL-loaded TPGS-based lipid nanoparticles (OXL/TLNP) was 1.12 μg/ml. The 3-fold lower IC50 value of OXL/TLNP indicates the superior anticancer effect of nanoparticle-based OXL. Consistently, OXL/TLNP induced a remarkable apoptosis of cancer cells. Approximately, ~52% of cells were in early apoptosis phase and ~13% of cells were in late apoptosis phase indicating the potent anticancer effect of the formulations. The findings from this study provide novel insights into the use of TPGS and lipid nanoparticle together for the better antitumor effect in colon cancers. Future studies will involve the detailed in vitro and in vivo studies on clinically relevant animals.

     

The BioGIT System: a Valuable <Emphasis Type="Italic">In Vitro</Emphasis> Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC_0–0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC_0–0.75h values were evaluated versus differences in AUC_0–1h and in AUC_0–2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC_0–0.75h, mean AUC_0–1h, and mean AUC_0–2h values were estimated using the lowest dose or the formulation with the lower AUC_0–0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC_0–0.75h ratios correlated significantly with log-transformed mean plasma AUC_0–1h ratios. Based on this correlation, BioGIT AUC_0–0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC_0–1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.     

The Immunosuppressive Activity of Polymeric Micellar Formulation of Cyclosporine A<Emphasis Type="Italic">: In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Studies

We have previously developed micelles of methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) as vehicles for the solubilization and delivery of cyclosporine A (CsA). These micelles were able to reduce the renal uptake and nephrotoxicity of CsA. The purpose of the current study was to test the efficacy of polymeric micellar formulation of CsA (PM-CsA) in suppressing immune responses by either T cells or dendritic cells (DCs). The performance of PM-CsA was compared to that of the commercially available formulation of CsA (Sandimmune®). Our results demonstrate that PM-CsA could exert a potent immunosuppressive effect similar to that of Sandimmune® both in vitro and in vivo. Both formulations inhibited phenotypic maturation of DCs and impaired their allostimulatory capacity. Furthermore, both PM-CsA and Sandimmune® have shown similar dose-dependent inhibition of in vitro T cell proliferative responses. A similar pattern was observed in the in vivo study, where T cells isolated from both PM-CsA-treated and Sandimmune®-treated mice have shown impairment in their proliferative response and IFN-γ production at similar levels. These results highlight the potential of polymeric micelles to serve as efficient vehicles for the delivery of CsA.     

Synthesis,Characterization and Biocompatibility of <Emphasis Type="BoldItalic">N</Emphasis>-palmitoyl L-alanine-based Organogels as Sustained Implants of Granisetron and Evaluation of their Antiemetic Effect

Purpose

To assess the gelation power of N-palmitoyl L-alanine derivatives in injectable oils and to use the best chosen organogel as parenteral implant of granisetron for the treatment of emesis.

Methods

Twelve N-palmitoyl L-alanine derived organogels were developed and evaluated in terms of morphology, thermal properties and in vivo performance. The ability of the selected formula to form in situ gel upon subcutaneous injection in rats and its biocompatibility were monitored over 2 weeks by histopathological examination of the injection site.

Results

The acid derivative (N-palmitoyl L-alanine; PA) was superior to ester derivatives. The chosen formula (PA/safflower oil 10% w/v) was successful in forming an in situ gel of granisetron when subcutaneously injected in rats, lasting for 2 weeks and proved to be biocompatible by histopathological examination. Moreover, it exerted an extended antiemetic activity by decreasing the cisplatin-induced pica for a duration of 96 h and reduced preprotachykinin A mRNA expression and Substance P level for up to 4 days (gastric tissue) or 5 days (medulla oblongata) in rats.

Conclusion

Granisetron organogel could be considered as a safe, sustained-release and supportive anticancer treatment in both acute and chronic emesis as well as an accompanying treatment with chemotherapeutics in cancer cases.

     

Development and Robustness Verification of an At-Line Transmission Raman Method for Pharmaceutical Tablets Using Quality by Design (QbD) Principles

Purpose

The purpose of the present study was to investigate the feasibility of developing a fast non-destructive at-line transmission Raman spectroscopy (TRS) method for core tablet potency and content uniformity (CU) as part of a real-time release testing (RTRt) control strategy.

Methods

The effects of tablet hardness and weight (thickness), API particle size, and concentration were studied by using a novel experimental design called generalized subset designs (GSDs). A subset of 28 experiments plus three replicate center points were selected for a total of 31 experiments. Matrix effects included tablets with active pharmaceutical ingredient (API) at seven concentration levels (14 to 26%w/w), and API particle size (17 to 71 μm), tablet weight (275 to 328 mg), and tablet hardness (8 to 16 SCU) at two levels.

Results

Three calibration models were developed, by using partial least squares (PLS) and different preprocessing conditions (model nos. 1 to 3). In model no. 1, all matrix effects were excluded. This model showed high potency prediction errors (RMSEP of 10.0%). When all matrix variations were included in the multivariate calibration according to the GSD as shown in model nos. 2 and 3, the prediction accuracy was greatly improved (RMSEP 2.56 and 1.74% respectively). The statistical significance of the tablet weight, hardness, and API particle size in the %Recovery (TRS vs. the reference HPLC method) was investigated by using MODDE Pro (Sartorius Stedim Data Analytics). Statistically significant effects were identified if the calculated p value was ≤?0.05. The main effect hardness, the cross-term hardness×particle size, and the quadratic term cal level×cal level showed to be statistically significant. However, these effects had a very small impact on tablet prediction accuracy (±?1.0%w/w) well within the intermediate precision of the method.

Conclusion

A non-destructive TRS method for core tablet potency and CU was fully validated, following ICH Q2 and EMEA NIR guidelines. The applicability of the method to process development batches was demonstrated and compared to a previously developed and validated NIR method.

     

Evaluations of the Effect of Sodium Metabisulphite on the Stability and Dissolution Rates of Various Model Drugs from the Extended Release Polyethylene Oxide Matrices

Purpose

This study examines the effect of sodium metabisulphite (SMB) as an antioxidant on the stability and release of various model drugs, namely, propranolol HCl, theophylline and zonisamide from the polyethylene oxide (PEO) tablets. The antioxidant was used to minimise degradation and instability of the manufactured tablets when stored at 40 °C (55 ± 5% RH) over 8 weeks.

Method

Multiple batches of tablets weighing 240 mg (50% w/w) with a ratio of 1:1 drug/polymer and 1% (w/w) sodium metabisulphite containing different model drugs and various molecular weights of PEO 750 and 303 were produced.

Results

The results indicated that the use of sodium metabisulphite marginally assisted in reducing drug release and degradation via oxidation in propranolol HCl tablets containing both PEO 750 and 303. In the case of poorly and semi-soluble drugs (zonisamide and theophylline), the formulations with both PEO showed entirely superimposable phenomenon and different release profiles compared to control samples (matrices without SMB). DSC study demonstrated the modifications of the polymer due to degradation and observed the effect of SMB on the thermal degradation of the PEO matrices.

Conclusion

The use of antioxidant has assisted in retaining the stability of the manufactured tablets with different model drugs especially those with the highly soluble drug that are susceptible to rapid degradation. This has been reflected by an extended release profile of various drugs used at various stages of the storage time up to 8 weeks.

     

Optimization of Process Parameters for Formulation of Ayurvedic Fermented Medicine <Emphasis Type="Italic">Arjunarishta</Emphasis> by Response Surface Methodology

Purpose

Utilization of traditional medicines increased worldwide. However, lack of modern technology creates problems for rejection of such preparations. Good manufacturing practices (GMPs) advocate uniformity and stability in the development of modern pharmaceuticals. Implementation of appropriate formulation strategies may enhance regulatory acceptance of complementary medicines. Herewith an attempt has been made to identify the impact of process parameter temperature, pH, and yeast cell number (inoculum volume) on manufacturing of ayurvedic fermented cardiotonic—arjunarishta.

Method

Optimization of the selected three process parameters was carried out for maximum production of alcohol in arishta using Box–Behnken design of response surface methodology with support of Design Expert software. Alcohol produced in formulation was detected after solvent extraction by dichromate oxidation method.

Result

Quadratic model was found significant with sum of squares 86.76 and F value 250.60. The incubation temperature 33.33 °C, pH 4.73, and inoculum volume 3.25 ml (4?×?10⁷ yeast cells/ml) have been identified as the best for maximal production of alcohol. It shows 7.68 % (v/v) production of alcohol which is identified by dichromate oxidation method. Presence of gallic acid also detected in optimized formulation by HPTLC with concentration 0.296 % (w/v).

Conclusion

This kind of study will definitely make formulation of arishta easier with higher consistency; moreover, manufacturing is possible in any season at any place.

     

Antimicrobial activity of Ankaferd Blood Stopper® against nosocomial bacterial pathogens

The aim of this study is to investigate the in vitro antimicrobial activity of Ankaferd Blood Stopper® against methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus species, Escherichia coli, Pseudomonas species, Acinetobacter species and Klebsiella species of nosocomial origin. Ankaferd inhibited growth in 72.4% to 100% of the bacteria tested, depending on the type of the isolate. As a result, it can be stated that Ankaferd inhibits the in vitro growth of nosocomial bacteria. This is a novel, important finding since severe hospital infections coexist with many hemostatic disorders, and the use of Ankaferd may increase hemostatic potential in such clinical conditions.