Downstream drug product processing of itraconazole nanosuspension: Factors influencing tablet material properties and dissolution of compacted nanosuspension-layered sugar beads.

There has been limited research done on the downstream processing of nanosuspensions into solid oral dosage forms. This paper demonstrates the bead layering process with a layering level at 150% and 240%, as well as the selection and justification of the outer phase excipients for tabletability and disintegrating properties. In a previous study, an itraconazole nanosuspension stabilised by SDS and HPMC E5 was layered onto sugar beads with coating polymer HPMC VLV. In the current study, compression studies with these layered beads utilising the small bead size at 150% or 240% layering levels with outer phase cushioning excipients MCC, copovidone or isomalt were performed. Other excipients such as co-compressed crospovidone-PEG 4000; DCP functioning as a disintegrant; and HPC as a binder was also added. Target output variables were achieved with a balance between an adequate tensile strength and fast dissolution rate with a release of 99.0% (±1.0% SD) within 10min, which is in accordance with the FDA guidance for dissolution testing. The results show that the compaction of nanosuspension-layered beads is a suitable process for processing an itraconazole nanosuspension into a solid dosage form such as a compacted tablet without compromising on drug release.

Downstream drug product processing of itraconazole nanosuspension: Factors influencing drug particle size and dissolution from nanosuspension-layered beads.

There is more research required to broaden the knowledge on the downstream processing of nanosuspensions into solid oral dosage forms, especially for coated nanosuspensions onto beads as carriers. This study focuses on bead layering as one approach to solidify nanosuspensions. The aim was to systematically investigate the influence of type of coating polymer (HPMC VLV vs. copovidone), bead material and bead size (sugar vs. MCC, and small vs. large) and coating thickness (50%-150% layering level) on the properties of a dried itraconazole nanosuspension. A stable itraconazole nanosuspension with a mean particle size below 200nm was prepared and a ratio of itraconazole and coating polymer of around 1:1 was identified. XRD and DSC scans revealed that itraconazole remained mostly crystalline after the bead layering process. The fastest dissolution rate was achieved using the small bead size, sugar beads, HPMC VLV as film-forming polymer and lowest layering level, with the best formulation releasing 94.1% (±3.45% SD) within the first 5min. A deterioration of the release profile with increasing layering level was only observed for MCC beads and was more pronounced when copovidone was used as a coating polymer. It was observed that bead layering is a suitable method to process an itraconazole nanosuspension into a solid form without compromising release.

A brief literature and patent review of nanosuspensions to a final drug product.

Particle size reduction can be used for enhancing the dissolution of poorly water-soluble drugs in order to enhance bioavailability. In nanosuspensions, the particle size of the drug is reduced to nanometer size. Nanosuspensions after downstream processing into drug products have successfully shown its impact on formulation design, the augmentation of product life cycle, patent life, and therapeutic efficacy. Formulation considerations for the nanosuspension formulation, its processing into a solid form, and aspects of material characterization are discussed. Technology assessments and feasibility of upstream processes for nanoparticle creation, and subsequently transformation into a drug product via the downstream processes have been reviewed. This paper aims to bridge formulation and process considerations along with patent reviews and may provide further insight into understanding the science and the white space. An analysis of current patent outlook and future trends is described to fully understand the limitations and opportunities in intellectual property generation.

Effect of binders on the release rates of direct molded verapamil tablets using twin-screw extruder in melt granulation.

Conventional manufacturing of pharmaceutical tablets often involves single processes such as blending, granulation, milling and direct compression. A process that minimizes and incorporates all these in a single continuous step is desirable. The concept of omitting milling step followed by direct-molding of tablets utilizing a twin-screw extruder in a melt granulation process using thermoplastic binders was explored. The objective of this study was to investigate the effect of combining hydrophilic binder (HPMC K4M, PEO 1M), and hydrophobic binder (Compritol® ATO 888, Precirol® ATO 5) on the release profiles of direct-molded tablets and direct-compressed tablets from milled extrudates using a quality-by-design approach. It was identified that hydrophilic binder type and process significantly affects (p=0.005) the release profiles of verapamil. Moreover, two-way interaction analysis demonstrated that the combination of process with type of hydrophilic polymer (p=0.028) and the type of hydrophilic polymer with polymer ratio (p=0.033) significantly affected the release profiles. The formulation release kinetics correlated to Higuchi release model and the mechanism correlated to a non-Fickian release mechanism. The results of the present study indicated that direct-molded tablets with different release profiles can be manufactured without milling process and through a continuous melt granulation using twin-screw extruder with appropriate thermoplastic binder ratio.

Transdermal delivery of haloperidol by proniosomal formulations with non-ionic surfactants.

Proniosomal formulations with non-ionic surfactant were studied. The effect of hydrophilicity and hydrophobicity of one or two surfactants on drug solubility, proniosome surface structure and stability and skin permeation of haloperidol from different formulations were investigated. Haloperidol (HP) was entrapped in proniosomes with very high efficiency for all formulations. Stability studies performed at 4 degrees C and 25 degrees C for a period of 6 weeks did not reveal any significant drug leakage (p>0.05). Formulations with single surfactants were found to increase the skin permeation of HP more than formulations containing two surfactants. The number of carbons in the alkyl chain of the non-ionic surfactant influenced the in vitro permeation of HP though the epidermis and the skin permeation was increased with increase in hydrophilic-lipophilic balance (HLB) value of the surfactant. Interfacial tension and surfactant hydrophobicity appeared to be useful for elucidating mechanism of skin permeation and for comparing drug fluxes from different proniosomal formulations.