Biorelevant test for supersaturable formulation.

Supersaturable formulation can generate supersaturation after dissolution, providing kinetic advantage in vivo. However, the supersaturation may precipitate before being absorbed, which makes it difficult to ensure and predict its in vivo performance. The traditional USP method is typically for Quality Control (QC) purpose and cannot be used to predict the formulation in vivo performance. Therefore, there is generally a lack of a predictive biorelevant testing method. In this review, different types of supersaturable formulations are described, including amorphous dispersions, polymorphs, salts/co-crystals, weak base and supersaturable solubilized formulations. Different kinds of in vitro dissolution methods for supersaturable formulations are also reviewed and discussed. Most of the methods take the physiology of gastrointestinal (GI) track into consideration, allowing reasonable prediction of the in vivo performance of supersaturable formulation. However, absorbing drug from GI track into blood stream is a complicate process, which can be affected by different in vivo processes such as transporter and metabolism. These factors cannot be captured by the in vitro testing. Thus, combining in vitro biorelevant dissolution methods with physiology-based pharmacokinetic modeling is a better way for the product development of supersaturable formulation.

The effect of bulking agents on the chemical stability of acid-sensitive compounds in freeze-dried formulations: sucrose inversion study.

The goal of the study was to evaluate the impact of amorphous bulking agents on the chemical stability of freeze-dried materials. Polyvinylpyrrolidone and dextran of different molecular weights and lactose were used as bulking agents, and sucrose was used as an example of an acid-sensitive compound. Lyophiles containing bulking agent and sucrose at 10:1 (w/w) ratio, citrate buffer, and optionally bromophenol blue (pH indicator) were tested by X-ray powder diffractometry, differential scanning calorimetry, and Karl Fischer titrimetry. Diffuse reflectance UV-vis spectroscopy was used to obtain the concentration ratio of the deprotonated (In(2-)) to the protonated (HIn(-)) indicator species, from which the Hammett acidity function (H(2-)) was calculated. The extent of sucrose inversion in lyophiles stored at 60 degrees C was quantified by HPLC. The bulking agent had a major impact on both the apparent solid-state acidity (H(2-)) and the degradation rate, with the degradation rate constants value highest for dextran lyophiles (most "acidic", lower H(2-)) followed by lactose and polyvinylpyrrolidone lyophile (least "acidic", higher H(2-)). The Hammett acidity function can be used as an empirical solid-state acidity scale, to predict the rank-order stability of acid-sensitive compounds in lyophiles prepared with different bulking agents.

Preparation of aminoglycoside-loaded chitosan nanoparticles using dextran sulphate as a counterion.

PURPOSE: To prepare aminoglycoside (AG) (streptomycin, gentamicin and tobramycin) loaded chitosan nanoparticles with high drug incorporation efficiency and test the in vivo oral efficacy of streptomycin (SM) loaded chitosan nanoparticles in a Mycobacterium tuberculosis (TB) chronic infection mouse model. METHOD: Dextran sulphate (a polyanion) was used to shield the positive charge of AG and increase the drug incorporation in the chitosan nanoparticle. By varying the concentration of each component, the formulation of SM-loaded chitosan nanoparticle was optimized by monitoring the drug incorporation efficacy and particle size. The mechanism of the nanoparticle formation was suggested and the preparation method was applied to two other aminoglycosides (AG): gentamicin (GM) and tobramycin (TM). The resulting nanoparticles were characterized by particle diameter, drug incorporation efficacy, drug loading efficacy and zeta potential. The in vitro drug release from these nanoparticles was carried out in pH 1.2 and pH 7.4 buffer. Preliminary in vivo oral efficacy studies of SM-loaded chitosan nanoparticles was performed in a Mycobacterium tuberculosis (TB) chronic infection mouse model. RESULTS: The optimal concentration of streptomycin (SM)/dextran sulphate/chitosan/tripolyphosphate (TPP) for SM nanoparticles preparation was 2/1.2/2/0.8 mg mL(-1). Through calculation, the optimal concentrations of dextran sulphate are 2.5 mg mL(-1) and 2.4 mg mL(-1) for 2 mg mL(-1) gentamicin and tobramycin, respectively (Table 1). The resulting AG chitosan nanoparticles had a high drug incorporation efficacy with particle sizes in the nanometre range. The in vitro drug release studies showed that more than 60% drug is retained inside the nanoparticles in pH 1.2 buffer after 6 h. The preliminary in vivo results indicated that oral SM chitosan nanoparticles induced one log 10 reduction (p < 0.01) in growth of the bacilli and were as effective as subcutaneously injected aqueous SM solution at the same concentration (100 mg kg(-1)). CONCLUSION: Dextran sulphate can significantly increase AG incorporation into the chitosan nanoparticles. The concentration of each component was critical in preparing AG-loaded chitosan nanoparticles. The chitosan nanoparticles designed in this study may provide a promising oral drug delivery formulation for AG which usually, in tuberculosis treatment, is administrated as an injectible preparation.

Stable-form screening: overcoming trace impurities that inhibit solution-mediated phase transformation to the stable polymorph of sulfamerazine.

Solution-mediated phase transformation (SMPT) has been used as a focused technique to rapidly identify the stable polymorph of a given substance. Despite ample precedence for acetonitrile being a good solvent for SMPT of sulfamerazine (SMZ), samples from specific lots of SMZ failed to convert from Form I to Form II after suspension for 2 weeks in acetonitrile. In these lots, an acetyl derivative of SMZ was identified and shown to impede transformation to the stable polymorph. The inhibitory effect of this impurity on polymorphic conversion was overcome with practical adjustments to experimental procedure, which hastened the kinetics of SMPT. The critical factors considered were (1) modifying the solvent to increase solubility, (2) minimizing the level of impurity in the slurries, (3) pre-treatment of the solid to quickly reach maximum supersaturation, and (4) temperatures that optimized kinetics as well as the free energy difference between enantiotropically related polymorphs.

A water-insoluble drug monolithic osmotic tablet system utilizing gum arabic as an osmotic, suspending and expanding agent.

A monolithic osmotic tablet system (MOTS) with two orifices in both side surfaces has been studied. Water-insoluble naproxen was selected as the model drug. Gum arabic was used as an osmotic, suspending and expanding agent, and cellulose acetate (CA) was used as semipermeable membrane. Polyethylene glycol 400 (PEG-400) was employed as plasticizer for controlling membrane porosity. The influences of gum arabic, PEG-400, membrane thickness and orifice size on the naproxen release profiles were investigated, and the optimal MOTS was evaluated in different environment media and stirring rates. The optimal MOTS was found to be able to deliver naproxen at a rate of approximately zero order up to 12 h in pH 6.8, cumulative release at 12 h is 81%, independent on environment media and stirring rate. Therefore, this MOTS can be used in oral drug-controlled delivery field, especially for water-insoluble drug.