Response surface methodology to optimize novel fast disintegrating tablets using ß cyclodextrin as diluent.

The objective of this work was to apply response surface approach to investigate main and interaction effects of formulation parameters in optimizing novel fast disintegrating tablet formulation using ß cyclodextrin as a diluent. The variables studied were diluent (ß cyclodextrin, X (1)), superdisintegrant (Croscarmellose sodium, X (2)), and direct compression aid (Spray dried lactose, X (3)). Tablets were prepared by direct compression method on B2 rotary tablet press using flat plain-face punches and characterized for weight variation, thickness, disintegration time (Y (1)), and hardness (Y (2)). Disintegration time was strongly affected by quadratic terms of ß cyclodextrin, croscarmellose sodium, and spray-dried lactose. The positive value of regression coefficient for ß cyclodextrin suggested that hardness increased with increased amount of ß cyclodextrin. In general, disintegration of tablets has been reported to slow down with increase in hardness. However in the present study, higher concentration of ß cyclodextrin was found to improve tablet hardness without increasing the disintegration time. Thus, ß cyclodextrin is proposed as a suitable diluent to achieve fast disintegrating tablets with sufficient hardness. Good correlation between the predicted values and experimental data of the optimized formulation validated prognostic ability of response surface methodology in optimizing fast disintegrating tablets using ß cyclodextrin as a diluent.

Application of hanging drop technique to optimize human IgG formulations.

OBJECTIVES: The purpose of this work is to assess the hanging drop technique in screening excipients to develop optimal formulations for human immunoglobulin G (IgG). METHODS: A microdrop of human IgG and test solution hanging from a cover slide and undergoing vapour diffusion was monitored by a stereomicroscope. Aqueous solutions of IgG in the presence of different pH, salt concentrations and excipients were prepared and characterized. KEY FINDINGS: Low concentration of either sodium/potassium phosphate or McIlvaine buffer favoured the solubility of IgG. Addition of sucrose favoured the stability of this antibody while addition of NaCl caused more aggregation. Antimicrobial preservatives were also screened and a complex effect at different buffer conditions was observed. Dynamic light scattering, differential scanning calorimetry and size exclusion chromatography studies were performed to further validate the results. CONCLUSIONS: In conclusion, hanging drop is a very easy and effective approach to screen protein formulations in the early stage of formulation development.

Effects of disintegration-promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets.

Effects of calcium silicate (disintegration-promoting agent) and various lubricants on an optimized beta-cyclodextrin-based fast-disintegrating tablet formulation were investigated. Effects of moisture treatment were also evaluated at 75, 85 and 95% relative humidities. A two factor, three levels (3(2)) full factorial design was used to optimize concentrations of calcium silicate and lubricant. Magnesium stearate, being commonly used lubricant, was used to optimize lubricant concentration in optimization study. Other lubricants were evaluated at an obtained optimum concentration. Desiccator with saturated salt solutions was used to analyze effects of moisture treatments. Results of multiple linear regression analysis revealed that concentration of calcium silicate had no effect; however concentration of lubricant was found to be important for tablet disintegration and hardness. An optimized value of 1.5% of magnesium stearate gave disintegration time of 23.4 s and hardness of 1.42 kg. At an optimized concentration, glycerol dibehenate and L-leucine significantly affected disintegration time, while talc and stearic acid had no significant effect. Tablet hardness was significantly affected with L-leucine, while other lubricants had no significant effect. Hardness was not affected at 75% moisture treatment. Moisture treatment at 85 and 95% increased hardness of the tablets; however at the same time it negatively affected the disintegration time.

Enhanced solubility and dissolution rate of lamotrigine by inclusion complexation and solid dispersion technique.

The solid-state properties and dissolution behaviour of lamotrigine in its inclusion complex with beta-cyclodextrin (betaCD) and solid dispersions with polyvinylpyrrolidone K30 (PVP K30) and polyethyleneglycol 6000 were investigated. The phase solubility profile of lamotrigine with betaCD was classified as AL-type, indicating formation of a 1:1 stoichiometry inclusion complex, with a stability constant of 369.96+/-2.26 M(-1). Solvent evaporation and kneading methods were used to prepare solid dispersions and inclusion complexes, respectively. The interaction of lamotrigine with these hydrophilic carriers was evaluated by powder X-ray diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry. These studies revealed that the drug was no longer present in crystalline state but was converted to an amorphous form. Among the binary systems tested, PVP K30 (1:5) showed greatest enhancement of the solubility and dissolution of lamotrigine.

Biochemical enhancement of transdermal delivery with magainin peptide: modification of electrostatic interactions by changing pH.

Magainin is a naturally occurring, pore-forming peptide that has recently been shown to increase skin permeability. This study tested the hypothesis that electrostatic forces between magainin peptides and drugs mediate drug transport across the skin. Electrostatic interaction between positively charged magainin and a negatively charged model drug, fluorescein, was attractive at pH 7.4 and resulted in a 35-fold increase in delivery across human epidermis in vitro when formulated with 2% N-lauroylsarcosine in 50% ethanol. Increasing to pH 10 or 11 largely neutralized magainin's charge, which eliminated enhancement due to magainin. Shielding electrostatic interactions with 1-2M NaCl solution similarly eliminated enhancement. Showing the opposite dependence on pH, electrostatic interaction between magainin and a positively charged anti-nausea drug, granisetron, was largely neutralized at pH 10 and resulted in a 92-fold increase in transdermal delivery. Decreasing to pH 5 increased magainin's positive charge, which repelled granisetron and progressively decreased transdermal flux. Circular dichroism analysis, multi-photon microscopy, and FTIR spectroscopy showed no significant pH effect on magainin secondary structure, magainin deposition in stratum corneum, or stratum corneum lipid order, respectively. We conclude that magainin increases transdermal delivery by a mechanism involving electrostatic interaction between magainin peptides and drugs.

Effect of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin complexation on physicochemical properties and antimicrobial activity of cefdinir.

The solid-state properties, dissolution profile and antimicrobial activity of inclusion complexes of cefdinir (CEF) with beta-cyclodextrin (betaCD) and hydroxypropyl beta-cyclodextrin (HPbetaCD) were investigated. The phase solubility profiles of cefdinir with betaCD and HPbetaCD were classified as A(L)-type, which indicates the formation of 1:1 stoichiometry inclusion complexes. Stability constants with 1:1 molar ratio obtained from the phase solubility diagrams were 120.38+/-1.07 and 58.60+/-1.20 M(-1) for betaCD and HPbetaCD, respectively. Binary systems of CEF with betaCD and HPbetaCD prepared by kneading method were characterized by Fourier transformation-infrared spectroscopy (FTIR) and X-ray powder diffractometry (XRD). The aqueous solubility of CEF was enhanced by 101% for betaCD and 23.4% for HPbetaCD, respectively. The dissolution profiles of inclusion complexes were determined and compared with those of CEF alone and their physical mixtures. The dissolution rate of CEF was increased by betaCD and HPbetaCD inclusion complexation moderately. However, the antimicrobial activity of CEF was increased significantly (p<0.001) by betaCD and HPbetaCD inclusion complexation against S. aureus and E. coli. In all these studies, HPbetaCD had superior antimicrobial activity than that of betaCD while betaCD had greater effect on solubility enhancement of CEF.

Direct quantitation of active ingredients in solid artesunate antimalarials by noncovalent complex forming reactive desorption electrospray ionization mass spectrometry.

The direct quantitation of active ingredients in solid pharmaceutical tablets by desorption electrospray ionization mass spectrometry (DESI MS) is complicated by the dependence of the DESI signal on variables such as spray angles and distances, morphological sample properties, and the difficulty of properly incorporating an internal standard. Here, a DESI MS method for the direct quantitative screening of widely counterfeited antimalarial tablets containing artesunate is presented. This method is based on reactive DESI, where analyte desorption and ionization occur by the formation of noncovalent complexes between alkylamine molecules in the DESI spray solution and artesunate molecules exposed on the sample surface in the open air. For quantitation purposes, the internal standard d4-artesunic acid was synthesized by esterification of d4-succinic anhydride and dihydroartemisinin, and homogeneously dispersed on the tablet surface via a controlled deposition procedure. The analyte-to-internal standard signal intensity ratio was observed to be largely independent of all DESI variables, only showing dependence on tablet hardness. Analysis of artesunate tablet standards prepared with known amounts of the active ingredient in the 0.02 to 0.32 mg artesunate mg(-1) tablet range resulted in a calibration curve with good linearity (r = 0.9985). Application of this method to the direct quantitation of genuine artesunate tablets from Vietnam showed a 6% (n = 4) precision and 94% accuracy after the spectral data were corrected for tablet hardness.