Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs.

Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C).

Application of melt granulation technology using twin-screw extruder in development of high-dose modified-release tablet formulation.

Development of modified-release oral tablets of drug products usually requires release-modifying polymers at the level of above 50% of the total weight. This makes the development of high-dose products, especially with doses in the range of 750-1000 mg, difficult because the tablet size becomes unacceptably high. This report presents the development of high-dose modified-release formulation of an active pharmaceutical ingredient (API), imatinib mesylate, with a drug load of approximately 90%, by melt granulation using a twin-screw extruder.

Application of melt granulation technology to enhance stability of a moisture sensitive immediate-release drug product.

The preparation of tablets by the melt granulation process was investigated to enhance chemical stability of a highly water-soluble drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor (Compound I), that is susceptible to degradation in presence of moisture. Melt granulation with a lipophilic binder (hydrogenated castor oil; Cutina HR) improved the stability of the drug, while still maintaining immediate-release characteristics of the drug product. The drug to binder ratio was shown to impact the degradation behavior of the drug product.

Developability assessment in pharmaceutical industry: An integrated group approach for selecting developable candidates.

This article describes the role and responsibilities of the Developability Assessment Group (DAG), a pharmaceutical Research and Development (R&D) subgroup, which supports drug discovery and development scientists with screening, developability assessment, and selection of new molecular entities (NMEs) for clinical studies. A strong collaboration between discovery group and DAG is essential for selecting the right NMEs for late-stage development, and consequently decreasing the NME attrition rate in late-stage development as well as in bringing down the associated cost and timelines. The investigations performed by DAG for evaluating research leads as well as the significance of these investigations in the developability assessment, the value of cutting edge tools and technologies, and the usefulness of the data in the decision making process are discussed in this review.

Robust calibration design in the pharmaceutical quantitative measurements with near-infrared (NIR) spectroscopy: Avoiding the chemometric pitfalls.

Quantification analysis with near-infrared (NIR) spectroscopy typically requires utilizing chemometric techniques, such as partial least squares (PLS) method, to achieve the desired selectivity. This article points out a major limitation of these statistical-based calibration methods. The limitation is that the techniques suffer from the potential for chance correlation.

Comprehensive validation scheme for in situ fiber optics dissolution method for pharmaceutical drug product testing.

There has been a growing interest during the past decade in the use of fiber optics dissolution testing. Use of this novel technology is mainly confined to research and development laboratories. It has not yet emerged as a tool for end product release testing despite its ability to generate in situ results and efficiency improvement.

Measurement of surface pH of pharmaceutical solids: a critical evaluation of indicator dye-sorption method and its comparison with slurry pH method.

Two methods for the measurement of surface pH of pharmaceutical solids, namely, the dye-sorption method and the slurry pH method, were compared. High purity drug substances, instead of excipients, were used as model solids, because acidic or basic impurities present in excipients could influence slurry pH. Solid test samples were prepared by sorption of methanol-water solutions of several indicator dyes, and their diffuse reflectance UV-visible spectra were measured.

Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form.

Tablet formulations of the maleate salt of a basic drug (I) showed a major loss in potency and a lack of mass balance upon storage under accelerated stability testing conditions. No such stability issues were observed in capsules that were compositionally similar, and even the tablet was stable when it was encapsulated in capsule shell. It was identified that the salt converts to its free base form in the microenvironment of the tablet formulation.

Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH.

Purpose: To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate.

Methods: pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions.

Phase behavior of amorphous molecular dispersions II: Role of hydrogen bonding in solid solubility and phase separation kinetics.

Purpose: To determine the factors influencing "solid solubility" and phase separation kinetics of drugs from amorphous solid dispersions.

Methods: Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single Tg were exposed to 40 degrees C/69% RH for 90 days.

Effect of combined use of nonionic surfactant on formation of oil-in-water microemulsions.

Purpose: This study evaluated the effects of combined use of two nonionic surfactants on the characteristics (i.e., appearance, emulsification time, and particle size) of oil-in-water microemulsions generated from flurbiprofen-loaded preconcentrates.

Phase behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility.

Purpose: To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis.

Methods: Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees C (69% RH) storage conditions, respectively.

Development of clinical dosage forms for a poorly water soluble drug I: Application of polyethylene glycol-polysorbate 80 solid dispersion carrier system.

Different formulation approaches were evaluated to ensure that the formulation of a poorly water soluble compound chosen during early development achieves optimum bioavailability. The insoluble compound has an aqueous solubility of 0.17 micro g/mL at 25 +/- 1 degrees C, a relatively high permeability (Caco2 P(app) = 6.