Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs.

Effect of geometry on drug release from 3D printed tablets.

Manufacture and characterization of mucoadhesive buccal films.

Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.

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3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics

Interest in hot-melt extrusion techniques for pharmaceutical applications is growing rapidly with well over 100 papers published in the pharmaceutical scientific literature in the last 12 years. Hot-melt extrusion (HME) has been a widely applied technique in the plastics industry and has been demonstrated recently to be a viable method to prepare several types of dosage forms and drug delivery systems. Hot-melt extruded dosage forms are complex mixtures of active medicaments, functional excipients, and processing aids. HME also offers several advantages over traditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, and the possibility of the formation of solid dispersions and improved bioavailability. This article, Part I, reviews the pharmaceutical applications of hot-melt extrusion, including equipment, principles of operation, and process technology. The raw materials processed using this technique are also detailed and the physicochemical properties of the resultant dosage forms are described. Part II of this review will focus on various applications of HME in drug delivery such as granules, pellets, immediate and modified release tablets, transmucosal and transdermal systems, and implants.

Pharmaceutical Applications of Hot-Melt Extrusion: Part I

Influence of plasticizers on the stability and release of a prodrug of Δ9-tetrahydrocannabinol incorporated in poly (ethylene oxide) matrices

Preformulation studies were performed on a hemiglutarate ester prodrug of Δ9-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a Tg close to 0°C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170°C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at −18°C but demonstrated higher degradation at 4°C, 25°C and 40°C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

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Preformulation Studies of a Prodrug of Δ9-Tetrahydrocannabinol

Chemical stability and bioadhesive properties of an ester prodrug of Delta 9-tetrahydrocannabinol in poly(ethylene oxide) matrices: effect of formulation additives.

The compatibility of promethazine hydrochloride (PMZ) with various tableting excipients has been investigated by isothermal stress testing (IST) and differential scanning calorimetry (DSC). DSC thermograms of PMZ and each of the excipients investigated were compared with their corresponding physical mixtures (1:1) for evaluation. Furthermore, Fourier transform infrared spectroscopy (FTIR) data was used to corroborate the results of DSC and IST. A preliminary sustained release tablet formulation of the drug, prepared using compatible excipients, was stored under accelerated storage conditions (40 degrees C/75% RH) and analyzed for stability, drug release and bioadhesion characteristics for up to 3 months. Based on DSC results alone, drug-excipient interactions were observed with Pearlitol SD200, lactose monohydrate and zinc stearate. Chromatographic analysis of the stressed binary mixture (stored at 55 degrees C for 3 weeks) containing PMZ-lactose monohydrate showed brown discoloration indicating potential interaction. However, stressed physical mixtures of PMZ-Pearlitol SD200 and PMZ-zinc stearate indicated compatibility as opposed to the thermal analysis. The tablet formulation was found to be very stable after 3 months of storage at accelerated stability conditions. Also, the release profiles and bioadhesive properties were found to be unaltered. Thus, both thermal and non-thermal methods were utilized to successfully evaluate the compatibility of excipients with PMZ and the tablet formulation was found to be stable.

Sridhar Thumma

Papers

Pharmaceutical Applications of Hot-Melt Extrusion: Part I

Influence of plasticizers on the stability and release of a prodrug of Δ9-tetrahydrocannabinol incorporated in poly (ethylene oxide) matrices

Preformulation Studies of a Prodrug of Δ9-Tetrahydrocannabinol

Chemical stability and bioadhesive properties of an ester prodrug of Delta 9-tetrahydrocannabinol in poly(ethylene oxide) matrices: effect of formulation additives.

Compatibility studies of promethazine hydrochloride with tablet excipients by means of thermal and non-thermal methods.