Quality by Design Empowered Development and Optimisation of Time-Controlled Pulsatile Release Platform Formulation Employing Compression Coating Technology.

The research was envisaged for development of time-controlled pulsatile release (PR) platform formulation to facilitate management of early morning chronological attacks. The development was started using prednisone as a model drug wherein core tablets were prepared using direct compression method and subsequently compression-coated with ethylcellulose (EC)-hydroxypropyl methylcellulose (HPMC) excipient blend. Initially, quality target product profile was established and risk assessment was performed using failure mode and effect analysis. In an endeavour to accomplish the objective, central composite design was employed as a design of experiment (DoE) tool. Optimised compression-coated tablet (CCT) exhibited 4-6 h lag time followed by burst release profile under variegated dissolution conditions viz. multi-media, change in apparatus/agitation and biorelevant media. Afterwards, five different drugs, i.e. methylprednisolone, diclofenac sodium, diltiazem hydrochloride, nifedipine and lornoxicam, were one-by-one incorporated into the optimised prednisone formula with replacement of former drug. Change in drug precipitated the issues like poor solubility and flow property which were respectively resolved through formulation of solid dispersion and preparation of active pharmaceutical ingredient (API) granules. Albeit, all drug CCTs exhibited desired release profile similar to prednisone CCTs. In nutshell, tour de force of research epitomised the objective of incorporating diverse drug molecules and penultimately obtaining robust release profile at varying dissolution conditions.

A newfangled study using risk silhouette and uncertainty approximation for quantification of acyclovir in diverse formulation.

Risk assessment and uncertainty approximation are two major and important parameters that need to be adopted for the development of pharmaceutical process to ensure reliable results. Additionally, there is a need to switch from the traditional method validation checklist to provide a high level of assurance of method reliability to measure quality attribute of a drug product. In the present work, evaluation of risk profile, combined standard uncertainty and expanded uncertainty in the analysis of acyclovir were studied. Uncertainty was calculated using cause-effect approach, and to make it more accurately applicable a method was validated in our laboratory as per the ICH guidelines. While assessing the results of validation, the calibration model was justified by the lack of fit and Levene׳s test. Risk profile represents the future applications of this method. In uncertainty the major contribution is due to sample concentration and mass. This work demonstrates the application of theoretical concepts of calibration model tests, relative bias, risk profile and uncertainty in routine methods used for analysis in pharmaceutical field.

Palatable reconstitutable dry suspension of artemether for flexible pediatric dosing using cyclodextrin inclusion complexation.

The present research was conducted to investigate the inclusion complexation of artemether (ARM) with beta-cyclodextrin (CD) with the aim of masking the bitterness along with improving the drug release and preparing a stable palatable formulation of ARM especially for pediatrics. A physical mixture and kneaded system were prepared to study the inclusion complexation. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on drug release. Reconstitutable dry suspension was evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, physical mixture and kneaded system exhibited improved drug release at pH, 1.2 and 6.8. To formulate palatable reconstitutable dry suspension of ARM, the 1:20M physical mixture was selected based on bitterness score. Reconstitutable dry suspension prepared using physical mixture (DS4), showed complete bitter taste masking, good flowability and ease of redispersibility. Taste evaluation of reconstitutable dry suspension in human volunteers rated tasteless with a score of 0 to DS4 and 3 to DS5 (reconstitutable dry suspension prepared using pure ARM). This conclusively demonstrated a stable and palatable reconstitutable dry suspension of ARM using CD inclusion complexation for flexible pediatric dosing.

Development and evaluation of sustained release gastroretentive minimatrices for effective treatment of H. pylori infection.

In the present work, sustained release gastroretentive minimatrices of amoxicillin have been designed and optimized using central composite design. Effect of amount of xanthan gum, rate controlling polymers (HPMC K100M CR/PEO coagulant (1:1)), carbopol 974P, and gas generating couple (sodium bicarbonate/citric acid (3:1)) was studied on dependent (response) variables, i.e., buoyancy lag time, drug release at 1 h, time required for 95% drug release, swelling index, and bioadhesive strength. Minimatrices were prepared by non aqueous granulation method using solution of PVP K30 in isopropyl alcohol. All the formulations were found to contain 99.2% to 100.9% of amoxicillin per minimatrix. Optimum formulation (Formulation number AGT09) containing high level of the independent variables was having buoyancy lag time of 7 min and drug release at 1 h was 32.5%. It required 9.39 h for 95% drug release while swelling index and bioadhesive strength were 341 and 17.9 dyn/cm(2), respectively. This formulation was said to be optimum because it has minimum buoyancy lag time, requires maximum time for 95% drug release, and has higher bioadhesive capabilities. In vitro results of an optimized formulation indicate its sustained drug release and gastric retention capability, which may be very useful for effective treatment of H. pylori infection.

Influence of chitosan crosslinking on bitterness of mefloquine hydrochloride microparticles using central composite design.

The present work examines the influence of various process and product parameters on mefloquine hydrochloride (MFL) entrapped in crosslinked chitosan microparticles for masking the bitterness. A central composite design (CCD) was employed to investigate the effect of three process and product variables, namely amount of MFL, chitosan and sodium hydroxide (crosslinking agent) on the incorporation efficiency, particle size, drug release at pH 6.8 and bitterness score. The microparticles were prepared by ionotropic gelation method, with a hardening time of 60 min. The optimum condition for process and product variables was evaluated using desirability function. The model is further cross validated for bias. The optimized microparticles were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the crosslinking of chitosan significantly affects incorporation efficiency, particle size, drug release and bitterness score. The bitterness score was decreased to zero compared to 3+ of pure MFL. It can be inferred that the proposed methodology can be used to prepare MFL microparticles for bitter taste masking.

Design and optimization of artemether microparticles for bitter taste masking.

The objective of the present investigation was to reduce the bitterness of artemether (ARM). Microparticles were prepared by the coacervation method using Eudragit E 100 (EE) as polymer and sodium hydroxide solution as nonsolvent for the polymer. A 32 full factorial design was used for optimization wherein the amount of drug (A) and polymer (B) were selected as independent variables and the bitterness score, particle size and drug release at pH, 1.2 and 6.8 were selected as dependent variables. Optimization was carried out using the desirability function. The optimized microparticles batch was characterized by FTIR and DSC. Multiple linear regression analysis revealed that reduced bitterness of ARM can be obtained by controlling the drug release of microparticles at pH 6.8 and increasing the amount of EE. The increase in the amount of polymer leads to reduction in drug release from microparticles at pH > 5 due to its insolubility and thus reduces bitterness. However, the increase in the amount of polymer results in improved dissolution, suggesting improved availability of ARM in stomach. Optimized microparticles prepared using 0.04 g of ARM and 15 mL of 1% (m/V) solution of EE showed complete bitter taste masking with improved drug release at pH 1.2.

Formulation and evaluation of primaquine phosphate taste-masked rapidly disintegrating tablet.

This work investigates the complete bitter-taste-masking of primaquine phosphate (PRM) using a solid dispersion with mono ammonium glycyrrhyzinate pentahydrate (GLY). This work also describes the preparation of rapidly disintegrating tablets (RDTs) of PRM by a direct compression method using superdisintegrant, croscarmellose sodium. A solid dispersion was prepared by the solvent evaporation method. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. In-vitro drug release studies were performed for RDTs at both pH 1.2 and 6.8. Bitterness score was evaluated using a human gustatory sensation test. FTIR spectroscopy and DSC showed no interaction of PRM in GLY solid dispersion. RDTs prepared from solid dispersion showed complete bitter-taste-masking of PRM. RDTs containing solid dispersion exhibited a better dissolution profile, at both pH 1.2 and 6.8, than pure PRM. Thus, the solid dispersion technique can be successfully used for complete bitter taste masking of PRM.

Formulation and evaluation of taste masked oral reconstitutable suspension of primaquine phosphate.

The purpose of this research was to mask the intensely bitter taste of primaquine phosphate (PRM) and to formulate suspension powder (cachets) of the taste masked drug. Taste masking was done using beta-cyclodextrin. To characterize and formulate taste masked cachets of PRM, the 1:25 M physical mixture was selected based on bitterness score. Phase solubility studies, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. Cachets were evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. Phase solubility studies showed weak interaction between PRM and CD. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, kneaded system and physical mixture exhibited better drug release at pH 1.2 and negligible effect at pH 6.8. Cachets prepared using physical mixture, (DS24), showed complete bitter taste masking and easy redispersibility. Taste evaluation of cachets in human volunteers rated tasteless with a score of 0 to DS24 and 3 to DS25. Thus, results conclusively demonstrated successful taste masking and formulation of cachets with taste masked drug.

Drug release and swelling kinetics of directly compressed glipizide sustained-release matrices: establishment of level A IVIVC.

The purpose of this study was to examine a level A in vitro-in vivo correlation (IVIVC) for glipizide hydrophilic sustained-release matrices, with an acceptable internal predictability, in the presence of a range of formulation/manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500, and lactose on in vitro release profiles was studied and fitted to various release kinetics models. Water uptake kinetics with scanning electron microscopy (SEM) was carried out to support the drug release mechanism. An IVIVC was established by comparing the pharmacokinetic parameters of optimized (M-24) and marketed (Glytop-2.5 SR) formulations after single oral dose studies on white albino rabbits. The matrix M-19 (xanthan:MCC PH301 at 70:40) and M-24 (xanthan:HPMC K4M:Starch 1500 at 70:25:15) showed the glipizide release within the predetermined constraints at all time points with Korsmeyer-Peppas' and zero-order release mechanism, respectively. Kopcha model revealed that the xanthan gum is the major excipient responsible for the diffusional release profile and was further supported by SEM and swelling studies. A significant level A IVIVC with acceptable limits of prediction errors (below 15%) enables the prediction of in vivo performance from their in vitro release profile. It was concluded that proper selection of rate-controlling polymers with release rate modifier excipients will determine overall release profile, duration and mechanism from directly compressed matrices.

Effect of chitosan crosslinking on bitterness of artemether using response surface methodology.

This work examines the influence of various process parameters on artemether entrapped in crosslinked chitosan microparticles for masking bitterness. A central composite design was used to optimize the experimental conditions for bitterness masking. Critical parameters such as the amounts of artemether, chitosan and crosslinking agent have been studied to evaluate how they affect responses such as incorporation efficiency, particle size and drug release at pH 6.8. The desirability function approach has been used to find the best compromise between the experimental results. The optimized microparticles were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the crosslinking of chitosan significantly affects incorporation efficiency, particle size and drug release at pH 6.8. The bitterness score of microparticles was decreased to 0, compared with 3+ for pure artemether. The proposed method completed masked the bitter taste of artemether.

Development and evaluation of artemether taste masked rapid disintegrating tablets with improved dissolution using solid dispersion technique.

The purpose of this research was to mask the intensely bitter taste of artemether (ARM) and to formulate a rapid-disintegrating tablet (RDT) of the taste-masked drug. Taste masking was done by solid dispersion with mono amino glycyrrhyzinate pentahydrate (GLY) by solvent evaporation method. To characterize and formulate taste masked rapid disintegrating tablets (RDTs) of ARM, the 1:1M solid dispersion was selected based on bitterness score. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. RDTs were evaluated for weight variation, disintegration time, hardness and friability. In vitro drug release studies were performed for RDTs at pH 1.2 and 6.8. Bitterness score was evaluated using mini-column method and compared with gustatory sensation test. FTIR spectroscopy and DSC showed no interaction while XRPD showed amorphization of ARM in GLY solid dispersion. RDTs prepared using solid dispersion, (RDT3), showed faster disintegration (within 28 s) and complete bitter taste masking of ARM. In addition, RDT3 exhibited better dissolution profile at both pH 1.2 and 6.8, than RDTs prepared from pure ARM (RDT5). Taste evaluation of RDTs in human volunteers rated tasteless with a score of 0 to RDT3 and 3 to RDT5. Mini-column revealed that RDT5 showed increase in number of persons who sensed bitterness with increased amount of ARM release while RDT3 sensed no bitterness. Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity with improved dissolution.

Design and optimization of mefloquine hydrochloride microparticles for bitter taste masking.

The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2), of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and sodium hydroxide as precipitant. A 3(2) full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent variables. The desirability function approach has been employed in order to find the best compromise between the different experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability, provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH.

Nateglinide quantification in rabbit plasma by HPLC: optimization and application to pharmacokinetic study.

A rapid, simple, and sensitive HPLC method with UV detection was developed and validated for the determination of nateglinide (NTG) from rabbit plasma. The retention behavior of NTG and gliclazide (GLZ, internal standard-IS) as a function of mobile phase pH, composition and flow rate was investigated. Separation was developed on a reverse-phase C(18) column (250 mm x 4.6mm i.d., 5 microm particle size), using a mixture of acetonitrile (ACN):10mM phosphate buffer (PBS, pH 3.0) in the ratio of 70:30(%v/v) at a flow rate of 1.0 ml/min with UV detection at 203 nm within 8 min, and quantified based on drug/IS peak area ratios. The plasma samples were prepared by a simple deproteinization with a mixture of methanol and acetonitrile, yielding more than 97.86% extraction efficiencies. The calibration curve was linear (correlation coefficient of 0.9984) in the concentration range of 10-2500 ng/ml. The limit of detection (LoD) and limit of quantitation (LoQ) were found to be 2.91 and 9.70 ng/ml, respectively. Both the intra-day and inter-day precisions at four tested concentrations were below 1.32% R.S.D. The present method was selective enough to analyze NTG in rabbit plasma without any tedious sample clean-up procedure and was successfully applied for estimating the pharmacokinetic parameters of NTG following oral administration of a single 15 mg NTG to white albino rabbits.

Reversed chitosan-alginate polyelectrolyte complex for stability improvement of alpha-amylase: optimization and physicochemical characterization.

The present work explores, using response surface methodology, the main and interaction effects of some process variables on the preparation of a reversed chitosan-alginate polyelectrolyte complex (PEC) with entrapped alpha-amylase for stability improvement. A 3(3) full factorial design was used to investigate the effect of the chitosan and alginate concentrations and hardening time on the percent entrapment, time required for 50% (T(50)) and 90% (T(90)) enzyme release, and particle size. The beads were prepared by dropping chitosan containing alpha-amylase into a sodium alginate solution without any salt. The in vitro enzyme release profile of the beads was fitted to various release kinetics models to study the release mechanism. A topographical characterization was carried out using scanning electron microscopy (SEM), and the entrapment was confirmed using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). Stability testing was carried out according to the International Conference on Harmonization (ICH) guidelines for zones III and IV. Beads prepared using 2.5%w/v chitosan and 3%w/v sodium alginate with a hardening time of 60 min had more than 90% entrapment and a T(90) value greater than 48 min. Moreover, the shelf-life of the enzyme-loaded beads was found to increase to 3.68 years, compared with 0.99 years for the conventional formulation. It can be inferred that the proposed methodology can be used to prepare a reversed PEC of chitosan and alginate with good mechanical strength, provided both the reactants are in a completely ionized form at the time of the reaction. Proper selection of the reaction pH, polymer concentration and hence charge density, and hardening time is important and determines the characteristics of the PEC.

Estimation of trace amounts of chromium(III) in multi-vitamin with multi-mineral formulations.

Two new specific, selective, simple and inexpensive spectroscopic methods for estimating a trace amount of chromium (Cr3+) from a multi-vitamin with multi-mineral pharmaceutical formulations were developed. The proposed methods are based on the conversion of Cr3+ to Cr6+ either by oxidation with a nitric acid-perchloric acid mixture (method I) or by fusion with an excess amount of sodium carbonate (method II), followed by the complexation of Cr6+ with 1,5-diphenylcarbazide (DPC) in a mineral acidic solution of pH 1.0 +/- 0.5. The pink-colored complex was estimated at 544 nm. Both methods were found to be linear in the range of 0.1 - 0.8 microg/ml with a limit of detection in the range of 0.0123 - 0.0157 microg/ml and a limit of quantitation in the range of 0.0419 - 0.0525 microg/ml. Method I was found to be suitable for estimating Cr3+ species in various formulations, like tablets, capsules and syrups, while method II was found to be suitable for tablets and capsules. Satisfactory recovery from spiked samples of standard Cr3+ suggests no interference of any excipients and diverse ions present in the formulations. The developed methods were compared with AAS by ANOVA, and no significant difference was observed.