Continuous twin screw melt granulation of glyceryl behenate: Development of controlled release tramadol hydrochloride tablets for improved safety.

Interest in granulation processes using twin screw extrusion machines is rapidly growing. The primary objectives of this study were to develop a continuous granulation process for direct production of granules using this technique with glyceryl behenate as a binder, evaluate the properties of the resulting granules and develop controlled release tablets containing tramadol HCl. In addition, the granulation mechanism was probed and the polymorphic form of the lipid and drug release rate were evaluated on stability. Granules were prepared using a Leistritz NANO16 twin screw extruder operated without a constricting die. The solid state of the granules were characterized by differential scanning calorimetry and X-ray diffraction. Formulated tablets were studied in 0.1N HCl containing 0-40% ethanol to investigate propensity for alcohol induced dose dumping. The extrusion barrel temperature profile and feed rate were determined to be the primary factors influencing the particle size distribution. Granules were formed by a combination immersion/distribution mechanism, did not require subsequent milling, and were observed to contain desirable polymorphic forms of glyceryl behenate. Drug release from tablets was complete and controlled over 16 h and the tablets were determined to be resistant to alcohol induced dose dumping. The drug release rate from the tablets was found to be stable at 40°C and 75% relative humidity for the duration of a 3 month study.

Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO.

CONTEXT: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge. OBJECTIVE: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000 mg) niacin sustained-release lipid matrix tablets. MATERIALS AND METHODS: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions. RESULTS: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12 h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000 mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000 mg. The tablets were stable for up to six months when stored at 25 and 40 °C. CONCLUSIONS: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced.

Effect of tablet structure on controlled release from supersaturating solid dispersions containing glyceryl behenate.

The objective of this study was to evaluate the use of glyceryl behenate as a plasticizer and release modifier in solid dispersion systems containing itraconazole and carbamazepine. Amorphous solid dispersions of high molecular weight polyvinylpyrrolidone were prepared by hot-melt extrusion, the processing of which was improved by the inclusion of glyceryl behenate. Dispersions were milled and subsequently compressed into tablets. Solid dispersions were also prepared by KinetiSol Dispersing, which allowed for the manufacture of monolithic tablets of the same composition and shape as compressed tablets. Tablets without glyceryl behenate and all compressed tablets were observed to have an incomplete release profile likely due to drug crystallization within the tablet as this occurred at conditions in which dissolution concentrations were below saturation. Monolithic tablets formulated to be more hydrophobic, by including glyceryl behenate, allowed for sustained release below and above saturation conditions.

Exploring the possible relationship between the drug release of Compritol®-containing tablets and its polymorph forms using micro X-ray diffraction.

Lipid excipients are more and more commonly used in the pharmaceutical industry as sustained drug delivery agents. However, their development may still be hindered by the well-known polymorphism of lipids which is perceived as a disadvantage with possible impact on drug release upon storage. In order to explore the eventual link between drug release modification and lipid polymorphism, we used a synchrotron radiation-based micro X-ray diffraction that allows probing the crystalline structures of the lipid matrix-forming excipient at a local scale and scanning it across the whole tablet. This technique demonstrated that only one polymorph of Compritol® 888 ATO is present in each tablet. This polymorph is identical whatever the compression force applied during the manufacturing is, and stays the same after storage at 40°C for 45days, even if these tablets exhibit different drug release profiles. Hence modification of drug release observed after storage is not due to lipid polymorphism. Implementation of post-compression thermal treatments generates another lipid polymorph. Again drug release is not linked with polymorphism because two different polymorphs of Compritol® 888 ATO lead to exactly the same dissolution profile. Variation of drug release observed during storage in accelerated conditions could be attributed to an altered distribution of the lipid component within the matrix structure. The lipid may flow within the matrix structure and increase the hydrophobicity of tablets.

Preparation and characterization of Compritol 888 ATO matrix tablets for the sustained release of diclofenac sodium.

The preparation of lipophilic matrix tablets for the sustained release of water soluble drugs via direct compression is not always feasible due to poor flow and rapid drug release. The aim was to evaluate the potential for developing sustained-release diclofenac sodium tablets, using Compritol® 888 ATO as a lipid matrix, by a wet granulation technique. The effects of wet granulation method (planetary mixer and fluid-bed) and liquid binder type (HPMC Metolose® 603, 606 or 615) on weight uniformity, tensile strength and release rates were investigated. The influence of compression force and speed during tablet manufacture under simulated rotary press production conditions were also evaluated. Rapid release of diclofenac sodium from directly compressed matrices was observed. A wet granulation technique using different HPMC binders produced free-flowing granules and matrices which released diclofenac sodium in a sustained manner over several hours. When the formulation comprising the lowest viscosity grade HPMC (Metolose® 603) was further evaluated using a laboratory scale fluid-bed system, consistently sized granules with good flowability and matrices with good weight uniformity and tensile strengths were produced. Release rates were consistent over a range of compression speeds and forces indicating the suitability of the formulation for production on a rotary tablet press.

Solid lipid excipients - matrix agents for sustained drug delivery.

Lipid excipients are attracting interest from drug developers due to their performance, ease of use, versatility and their potential to generate intellectual property through innovation in drug delivery particularly in the case of modifying drug release systems. Many articles have described the use of lipid excipients to develop matrix modified release dosage forms in a range of processing techniques, therefore a comprehensive review is timely to collect together and analyze key information. This review article focuses on the utility of lipid excipients in solid sustained drug delivery systems with emphasis on the efficiency and robustness of these systems with respect to: (i) the choice of the manufacturing process and impact on drug release, (ii) the fundamental drug release mechanisms, (iii) resistance of the drug formulation under physiological conditions and (iv) long-term stability. Understanding the functionality of these versatile excipients in formulation is elementary for the development of highly robust lipid-based sustained release medicines.