Sailesh A. Varia

Role of tumor vascular architecture in drug delivery

Tumor targeted drug delivery has the potential to improve cancer care by reducing non-target toxicities and increasing the efficacy of a drug. Tumor targeted delivery of a drug from the systemic circulation, however, requires a thorough understanding of tumor pathophysiology. A growing or receding (under the impact of therapy) tumor represents a dynamic environment with changes in its angiogenic status, cell mass, and extracellular matrix composition. An appreciation of the salient characteristics of tumor vascular architecture and the unique biochemical markers that may be used for targeting drug therapy is important to overcome barriers to tumor drug therapy and to facilitate targeted drug delivery. This review discusses the unique aspects of tumor vascular architecture that need to be overcome or exploited for tumor targeted drug delivery.

Physical interactions of magnesium stearate with starch-derived disintegrants and their effects on capsule and tablet dissolution

Abstract Overmixing of magnesium stearate with granules in the hopper of a capsule filling machine can slow down their dissolution because of coating by magnesium stearate, which acts as a water repellant. This phenomenon was systematically investigated using three active ingredients representing a wide range of solubility in 0.1 N hydrochloric acid, the dissolution medium. The active ingredients were hydrochlorothiazide, an antiviral agent SQ32756 (BV-araU), and aztreonam, with solubilities in 0.1 N hydrochloric acid of 0.6, 5.0 and 12 mg/ml, respectively, at 37°C. When capsules of an aqueous wet granulated formulation containing one of the aforementioned active ingredients, hydrous lactose, pregelatinized starch, microcrystalline cellulose, and 1% w/w magnesium stearate were filled using the MG2 Futura capsule filler, capsules from the latter part of the filling run exhibited significantly slower dissolution compared to those from the beginning. The extent of slowdown in dissolution of the capsules varied depending upon the aqueous solubility of the active ingredient. The slowdown was maximum for hydrochlorothiazide capsules followed by SQ32756 and aztreonam capsules, respectively. Further studies using SQ32756 as the active ingredient indicated that replacement of magnesium stearate in the formulation with other hydrophobic lubricants such as calcium or zinc stearate gave similar results. However, replacement of magnesium stearate with hydrophilic lubricants such as Stear-O-Wet® or sodium stearyl fumarate did not result in a slowing of dissolution. Among the hydrophobic lubricants, magnesium stearate caused the maximum slowdown in dissolution, followed by zinc and calcium stearates, respectively. This observed rank order was correlated to the surface area of these lubricants. Furthermore, optimization of magnesium stearate concentration to 0.25% w/w provided enough lubrication for capsule filling while resulting in a capsule with satisfactory dissolution. Replacement of pregelatinized starch by starch-derived superdisintegrants such as Explotab® or Primojel® also resulted in no slowing of dissolution of capsules, even after overmixing with 1% w/w magnesium stearate. Although the granules overmixed with 1% w/w hydrophobic lubricants exhibited slow down in dissolution when filled into capsules, tablets compressed from these granules dissolved rapidly.

Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation.

Three model compounds were used to study the effect of process parameters on in-process critical material attributes and a final product critical quality attribute. The effect of four process parameters was evaluated using design of experiment approach. Batches were characterized for particle size distribution, density (porosity), flow, compaction, and dissolution rate. The mechanisms of the effect of process parameters on primary granule properties (size and density) were proposed. Water amount showed significant effect on granule size and density. The effect of impeller speed was dependent on the granule mechanical properties and efficiency of liquid distribution in the granulator. Blend density was found to increase rapidly during wet massing. Liquid addition rate was the least consequential factor and showed minimal impact on granule density and growth. Correlations of primary properties with granulation bulk powder properties (compaction and flow) and tablet dissolution were also identified. The effects of the process parameters on the bulk powder properties and tablet dissolution were consistent with their proposed link to primary granule properties. Understanding the impact of primary granule properties on bulk powder properties and final product critical quality attributes provides the basis for modulating granulation parameters in order to optimize product performance.

Drug Excipient Interactions

Unintended physicochemical interaction of an excipient with a drug substance in a dosage form can result in the complexation or binding of the drug, resulting in slow and/or incomplete drug release in a dissolution medium. It is important to assess the risk whether such interactions would reduce oral bioavailability of a drug from its dosage form. This chapter describes the development of a methodology to assess the biorelevance of the drug release impact of drug-excipient binding interactions using a model compound, brivanib alaninate. This methodology was developed using a combination of modeling and simulation tools as well as experimental data generated in vitro and in vivo. In addition, general application of this principle and methodology to other drug substances and binding affinities of drugs with excipients as a function of dose is described.

Characterization of humidity-dependent changes in crystal properties of a new HMG-CoA reductase inhibitor in support of its dosage form development

Abstract Humidity-dependent changes in the crystal properties of the disodium salt of a new HMG-CoA reductase inhibitor (SQ-33600) were characterized using a combination of gravimetric, thermal, and spectral techniques. The drug substance was found to exhibit rapid moisture sorption and/or desorption, depending on the environmental conditions. Three crystalline solid hydrates and one liquid crystalline phase were identified, each having a definite stability over a range of humidity. The drug substance turned amorphous upon wet granulation, and the amorphous phase reconverted to crystalline hydrates upon exposure to 33–75% relative humidity. To avoid physical instability of dosage forms due to phase changes, manufacturing of solid dosage forms by dry processing below 52% relative humidity was recommended. The dissolution of drug from solid dosage forms was observed to be independent of the crystal form of the active.

Formation of reactive impurities in aqueous and neat polyethylene glycol 400 and effects of antioxidants and oxidation inducers

A 2,4-dinitrophenylhydrazine (DNPH) precolumn derivatization high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method was developed to quantify levels of formaldehyde and acetaldehyde in polyethylene glycol (PEG) solutions. Formic acid and acetic acid were quantified by HPLC-UV. Samples of neat and aqueous PEG 400 solutions were monitored at 40°C and 50°C to determine effects of excipient source, water content, pH, and trace levels of hydrogen peroxide or iron metal on the formation of reactive impurities. The effects of antioxidants were also evaluated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, especially formic acid as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. A distribution of unidentified degradation products formed in neat PEG 400 disappeared upon addition of HCl with corresponding increase of formic acid, indicating they were likely to be PEG-formyl esters. Other unidentified degradation products reacted with DNPH to form a distribution of derivatized products likely to be PEG aldehydes. Antioxidants butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate d-alpha tocopheryl polyethylene glycol-1000 succinate, and sodium metabisulfite were effective in limiting reactive impurity formation, whereas ascorbic acid and acetic acid were not.

Study of Phase Behavior of Poly(ethylene glycol)–Polysorbate 80 and Poly(ethylene glycol)–Polysorbate 80–Water Mixtures

Mixtures of poly(ethylene glycols) (PEGs) with polysorbate 80 are often used to dissolve poorly water-soluble drugs in dosage forms, where polysorbate 80 helps either in enhancing dispersion or in inhibiting precipitation of drugs once the solution is mixed with water. Binary phase diagrams of polysorbate 80 with several low molecular weight PEGs and a ternary phase diagram of polysorbate 80 with PEG 400 and water are presented. Two phases were observed in the binary mixtures when the concentration of PEG 200, PEG 300, PEG 400, or PEG 600 was >55%(w/w). The miscibility of the binary mixtures increases with an increase in temperature; the upper consolute temperatures of PEG 200-polysorbate 80, PEG 300-polysorbate 80, PEG 400-polysorbate 80, and PEG 600-polysorbate 80 mixtures were 100, 85, 75, and 40 degrees C, respectively. The upper consolute temperature of PEG 1000-polysorbate 80 could not be determined because the melting temperature of the mixtures is approximately 40 degrees C and the consolute temperature appeared to be less than this temperature. The decrease in upper consolute temperature with an increase in PEG molecular weight indicated a greater miscibility of the two components. In the ternary system, phase separation of polysorbate 80 was observed when the concentration of PEG 400 was >50-60 % (w/w), possibly because of the high exclusion volume of PEG 400.

Photostabilization of uncoated tablets of sorivudine and nifedipine by incorporation of synthetic iron oxides

Abstract The synthetic iron oxides are strong absorbers of radiation wavelengths below 400 nm. They also have great hiding power due to their high refractive indices and high tinctorial capacity. These properties of iron oxides were utilized in Photostabilization of two light-sensitive drugs, sorivudine (BV-araU) and nifedipine. Light stability studies on 10 mg potency aqueous wet granulated uncoated tablets of sorivudine and nifedipine formulated with or without 0.2% w/w yellow iron oxide were performed by exposing them directly to room light and/or light of 400 foot candle intensity. Subsequent to exposure, they were assayed for loss in potency and increase in level of degradants due to photodecomposition. Uncoated tablets containing 0.2% w/w yellow iron oxide were found to be more light stable than those without it. The effect of incorporation of 0.2% w/w yellow iron oxide in the tablet core on photolytic degradation was also compared with that of a film coated tablet. Inclusion of 0.2% w/w yellow, red, or black iron oxide into uncoated tablets provided more light protection than 11% w/w coating with Opadry® white. Furthermore, inclusion of a combination of 0.05% w/w red and 0.04% w/w yellow iron oxides into uncoated tablets gave them more light protection than the inclusion of either 0.2% w/w yellow or red iron oxide alone.

Effects of different types of lactose and disintegrant on dissolution stability of hydrochlorothiazide capsule formulations

Dissolution at the 20 min time point of hydrochlorothiazide (HCTZ) capsules containing Fast-Flo® lactose, hydrous lactose, or anhydrous lactose decreased by 45, 25, and 10%, respectively, after 6 months storage at 50°C. It was hypothesized that the decrease in dissolution was due to the formation of a trace amount of formaldehyde from the hydrolysis of HCTZ in the presence of moisture liberated from the excipients and the capsule shells, and the subsequent interactions of the formaldehyde with gelatin capsule shells and corn starch present in the formulation to form insoluble compounds. In a simulated storage environment of high temperature and moisture in Conway cells and using the diffusion method, it was demonstrated that the amount of formaldehyde formed depended on the type of lactose used in the blend and followed the rank order of Fast-Flo® > hydrous > anhydrous (pairwise p values < 0.05). In the capsule formulation containing Fast-Flo® lactose as diluent, replacement of corn starch with a superdisintegrant such as sodium starch glycolate (Explotab®) or croscarmellose sodium (Ac-Di-Sol®) did not improve the dissolution stability. However, replacement of corn starch with crospovidone (Polyplasdone XL®) as a disintegrant resulted in a capsule formulation with satisfactory dissolution stability. It was observed that in formulations which exhibited poor dissolution, the dissolution of the capsule shells was more adversely affected by formaldehyde than that of the capsule contents. Moreover, in the presence of added water, significantly less formaldehyde was detected in blends containing corn starch, Explotab®, or Ac-Di-Sol® compared to blends containing Polyplasdone XL® or control (no disintegrant) probably because some of the formaldehyde generated was consumed in reactions with those disintegrants. Success of Polyplasdone XL® in improving dissolution stability of the HCTZ capsules was attributed mainly to its moisture scavenging ability, which prevented the formation of formaldehyde and, to some extent, its non-reactivity with formaldehyde.

An evaluation of process parameters to improve coating efficiency of an active tablet film-coating process

Effects of material and manufacturing process parameters on the efficiency of an aqueous active tablet film-coating process in a perforated pan coater were evaluated. Twenty-four batches representing various core tablet weights, sizes, and shapes were coated at the 350-500 kg scale. The coating process efficiency, defined as the ratio of the amount of active deposited on tablet cores to the amount of active sprayed, ranged from 86 to 99%. Droplet size and velocity of the coating spray were important for an efficient coating process. Factors governing them such as high ratios of the suspension spray rate to atomization air flow rate, suspension spray rate to pattern air flow rate, or atomization air flow rate to pattern air flow rate improved the coating efficiency. Computational fluid dynamics modeling of the droplets showed that reducing the fraction of the smaller droplets, especially those smaller than 10 μm, resulted in a marked improvement in the coating efficiency. Other material and process variables such as coating suspension solids concentration, pan speed, tablet velocity, exhaust air temperature, and the length of coating time did not affect the coating efficiency profoundly over the ranges examined here.