Mohammad Azad

Redispersible fast dissolving nanocomposite microparticles of poorly water-soluble drugs.

Enhanced recovery/dissolution of two wet media-milled, poorly water-soluble drugs, Griseofulvin (GF) and Azodicarbonamide (AZD), incorporated into nanocomposite microparticles (NCMPs) via fluidized bed drying (FBD) and spray-drying (SD) was investigated. The effects of drying method, drug loading, drug aqueous solubility/wettability as well as synergistic stabilization of the milled suspensions on nanoparticle recovery/dissolution were examined. Drug nanoparticle recovery from FBD and SD produced NCMPs having high drug loadings was evaluated upon gentle redispersion via optical microscopy and laser diffraction. During wet-milling, hydroxypropyl cellulose (HPC) alone stabilized more wettable drug (AZD) nanoparticles with slight aggregation, but could not prevent aggregation of the GF nanoparticles. In contrast, well-dispersed, stable nanosuspensions of both drugs were produced when sodium dodecyl sulfate (SDS) and HPC were combined. The FBD and SD NCMPs without SDS exhibited incomplete nanoparticle recovery, causing slower dissolution for GF, but not for AZD, likely due to higher aqueous solubility/wettability of AZD. For high active loaded NCMPs (FBD ∼50 wt%, SD ∼80 wt%) of either drug, HPC-SDS together owing to their synergistic stabilization led to fast redispersibility/dissolution, corroborated via optical microscopy and particle sizing. These positive attributes can help development of smaller, high drug-loaded dosage forms having enhanced bioavailability and better patient compliance.

Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants

Abstract Nanocomposite microparticles (NCMPs) incorporating drug nanoparticles and wet-milled swellable dispersant particles were investigated as a surfactant-free drug delivery vehicle with the goal of enhancing the nanoparticle recovery and dissolution rate of poorly water-soluble drugs. Superdisintegrants were used as inexpensive, model, swellable dispersant particles by incorporating them into NCMP structure with or without wet-stirred media milling along with the drug. Suspensions of griseofulvin (GF, model drug) along with various dispersants produced by wet-milling were coated onto Pharmatose® to prepare NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, superdisintegrant) and Mannitol were used as additional dispersants to prepare surfactant-free NCMPs. Nanoparticle recovery during redispersion and dissolution of the various GF-laden NCMPs were examined. Suspensions prepared by co-milling GF/HPC/CCS or milling GF/HPC/SDS were stable after 30 h of storage. After drying, due to its extensive swelling capacity, incorporation of wet-milled CCS in the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, ultimately leading to fast recovery of the GF nanoparticles. Optimized wet co-milling and incorporation of CCS in NCMP structure led to superior dispersant performance over incorporation of unmilled CCS or physically mixed unmilled CCS with NCMPs. The enhanced redispersion correlated well with the fast GF dissolution from the NCMPs containing either CCS particles or SDS. Overall, swellable dispersant (CCS) particles, preferably in multimodal size distribution, enable a surfactant-free formulation for fast recovery/dissolution of the GF nanoparticles.

Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

Drug nanoparticles in suspensions can form aggregates leading to physical instability, which is traditionally mitigated using soluble polymers and surfactants. The aim of this paper was to explore common superdisintegrants, i.e., sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP), as novel class of dispersants for enhanced stabilization of fenofibrate (FNB), a model BCS Class II drug, suspensions. FNB was wet-milled with superdisintegrants along with hydroxypropyl methylcellulose (HPMC), a soluble adsorbing polymer, in a stirred media mill. For comparison, FNB was also milled in the presence of HPMC and/or SDS (sodium dodecyl sulfate) without superdisintegrants. Laser diffraction, scanning electron microscopy, viscometry, differential scanning calorimetry, and powder X-ray diffraction were used to characterize the suspensions. The results show that 2% HPMC along with 1% SSG or 1% CCS mitigated the aggregation of FNB nanoparticles significantly similar to the use of either 5% HPMC or 1% HPMC-0.075% SDS, whereas CP was not effective due to its low swelling capacity. CCS/SSG enhanced steric-kinetic stabilization of the FNB suspensions owing to their high swelling capacity, viscosity enhancement, and physical barrier action. Overall, this study provides a mechanistic basis for a novel method of formulating surfactant-free drug nanosuspensions with co-milled superdisintegrants.

Nanomilling of Drugs for Bioavailability Enhancement: A Holistic Formulation-Process Perspective

Preparation of drug nanoparticles via wet media milling (nanomilling) is a very versatile drug delivery platform and is suitable for oral, injectable, inhalable, and buccal applications. Wet media milling followed by various drying processes has become a well-established and proven formulation approach especially for bioavailability enhancement of poorly water-soluble drugs. It has several advantages such as organic solvent-free processing, tunable and relatively high drug loading, and applicability to a multitude of poorly water-soluble drugs. Although the physical stability of the wet-milled suspensions (nanosuspensions) has attracted a lot of attention, fundamental understanding of the process has been lacking until recently. The objective of this review paper is to present fundamental insights from available published literature while summarizing the recent advances and highlighting the gap areas that have not received adequate attention. First, stabilization by conventionally used polymers/surfactants and novel stabilizers is reviewed. Then, a fundamental understanding of the process parameters, with a focus on wet stirred media milling, is revealed based on microhydrodynamic models. This review is expected to bring a holistic formulation-process perspective to the nanomilling process and pave the way for robust process development scale-up. Finally, challenges are indicated with a view to shedding light on future opportunities.

Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving, high drug-loaded, surfactant-free nanocomposites

Abstract Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.

Fast dissolution of poorly water soluble drugs from fluidized bed coated nanocomposites: Impact of carrier size

Formation of core-shell nanocomposites of Fenofibrate and Itraconazole, model poorly water soluble drugs, via fluidized bed (FB) coating of their well-stabilized high drug loaded nanosuspensions is investigated. Specifically, the extent of dissolution enhancement, when fine carrier particles (sub-50μm) as opposed to the traditional large carrier particles (>300μm) are used, is examined. This allows testing the hypothesis that greatly increased carrier surface area and more importantly, thinner shell for finer carriers at the same drug loading can significantly increase the dissolution rate when spray-coated nanosuspensions are well-stabilized. Fine sub-50μm lactose (GranuLac® 200) carrier particles were made fluidizable via dry coating with nano-silica, enabling decreased cohesion, fluidization and subsequent nanosuspension coating. For both drugs, 30% drug loaded suspensions were prepared via wet-stirred media milling using hydroxypropyl methyl cellulose and sodium dodecyl sulfate as stabilizers. The stabilizer concentrations were varied to affect the milled particle size and prepare a stable nanosuspension. The suspensions were FB coated onto hydrophilic nano-silica (M-5P) dry coated sub-50μm lactose (GranuLac® 200) carrier particles or larger carrier particles of median size >300μm (PrismaLac®40). The resulting finer composite powders (sub-100μm) based on GranuLac® 200 were freely flowing, had high bulk density, and had much faster, immediate dissolution of the poorly water-soluble drugs, in particular for Itraconazole. This is attributed to a much higher specific surface area of the carrier and corresponding thinner coating layer for fine carriers as opposed to those for large carrier particles.

Preparation of concentrated stable fenofibrate suspensions via liquid antisolvent precipitation

Abstract A major challenge in achieving size stability for relatively high concentration of fine particles from poorly water-soluble drug fenofibrate (FNB) is addressed through T-mixing based liquid antisolvent precipitation in the presence of ultrasonication and judicious use of stabilizers. Multiple stabilizers were screened in a batch mode prior to their continuous formation via T-mixing. In both cases, the stable suspensions maintained their size after 2 days of storage at room temperature, with the smallest particle size of d50: ∼1.2 µm was achieved through a combination of HPMC with SDS or PF-68. The influence of processing parameters, such as sonication energy, sonication probe insert depth and solvent/antisolvent flow rate, on the particle size distribution (PSD) in T-mixing were investigated, to identify optimum processing conditions. Optimal operating and formulation conditions also allowed increase in the drug loading from 0.32% to 4% (w/v), while keeping the median size 2.5 µm. Interestingly, the primary particles observed in the SEM were spherical and under 100 nm in diameter, indicating agglomeration. It was shown that the stabilized particles could be centrifuged and did not show size growth upon resuspension, allowing for increase in the drug loading up to 27% (w/v), which is a significant novel outcome.

Stable and Fast-Dissolving Amorphous Drug Composites Preparation via Impregnation of Neusilin® UFL2

A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin®. The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs.