Formulation Intervention to Overcome Decreased Kinetic Solubility of a Low Tg Amorphous Drug.

This technical note investigated the loss of dissolution rate during accelerated stability studies with a dry blend capsule formulation containing an amorphous salt of drug NVS-1 (Tg 76°C). After 6 m at 40°C/75%RH, dissolution of NVS-1 was ≤40% of initial value. Scanning electron microscope characterization of the undissolved capsule contents from samples stored at 50°C/75%RH for 3 weeks showed agglomeration with a distinct "melt and fuse" morphology of particles. At elevated temperature and humidity conditions, undesired sintering among the amorphous drug particles was observed. Humidity plasticizes the drug as the stability temperature (T) gets closer to the glass transition temperature (Tg) of the amorphous salt (i.e., smaller Tg-T); a decreased viscosity favors viscoplastic deformation and sintering of drug particles. When moisture is adsorbed onto agglomerated drug particles, partial dissolution of the drug forms a viscous surface layer, further reducing the rate of dissolution media penetration into the bulk solid, hence the slower dissolution rate. Formulation intervention focused on the use of L-HPC and fumed silica as disintegrant and glidant and the removal of the hygroscopic crospovidone. Reformulation improved dissolution performance at short-term accelerated stability conditions of 50°C (± 75%RH); however, sintering to a lesser extent was still observed at high humidity, impacting the dissolution rate. We infer reducing the impact of moisture at high humidity conditions in a formulation with a 34% drug load is challenging. Future formulation efforts will focus on the addition of water scavengers, reducing drug load by ~50% to physically separate drug particles by water-insoluble excipients, and optimizing disintegrant levels.

To crush or not to crush: A brief review of novel tablets and capsules prepared from nanocrystal and amorphous solid dispersion technologies.

PURPOSE: To educate healthcare professionals regarding the risks of manipulating drug products formulated via nanocrystal or amorphous solid dispersion technologies. SUMMARY: Recent pharmaceutics innovations such as nanocrystals and amorphous solid dispersions have been used successfully to improve oral bioavailability of drugs. Over 30 drug products based on these technologies have been approved by the Food and Drug Administration, and more are in the development pipeline. While these products are similar in appearance to traditional tablets or capsules, they should not be crushed or suspended in liquid vehicles. Such manipulations can compromise the integrity of the formulation and subsequently alter the oral bioavailability. It is alarming that the majority of these products are not included in the Institute for Safe Medication Practices (ISMP) "Do Not Crush" list. A summary drug table is presented in this article to provide accurate information for pharmacists and other healthcare providers. CONCLUSION: Novel formulations of tablets and capsules are being used to increase the oral bioavailability of certain drugs. Crushing these products can significantly alter product performance and clinical outcomes. We encourage ISMP to add these drug products to the Do Not Crush list due to wide use of this list throughout healthcare. In the meantime, pharmacists should be mindful of the new formulation technologies and advocate for the proper use of these drug products.

Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders.

Daily intravenous arsenic trioxide administered with all-trans retinoid acid, the standard-of-care for acute promyelocytic leukemia, is costly and challenging to administer. ORH-2014 is a novel, oral arsenic trioxide formulation, consisting of micron-size drug particles with rapid dissolution and high bioavailability. We conducted a multicenter phase 1 dose-escalating study in patients with advanced hematologic malignancies. Twelve patients received ORH-2014 at 5 mg (n=3), 10 mg (n=6), or 15 mg (n=3) orally once a day (fasted state). Objectives were to assess the safety, tolerability and pharmacokinetics of ORH-2014 to support a dose recommendation for future trials. The median age of the patients was 77 years (range: 45-81) and they had received a median of two (range: 1-5) prior therapies. There were no dose limiting toxicities and no drug-related severe adverse events, except one grade III QT prolongation occurring beyond the dose limiting toxicity assessment period and resolving after treatment interruption. ORH-2014 steady-state plasma concentration was reached on day 15. ORH-2014, 15 mg Cmax was comparable to the calculated approved dose of intravenous arsenic trioxide (mean [% coefficient of variation]: 114 [21%] vs 124 [60%] ng/mL) and area under the curve from 0 to 24 hours was 2,140 (36%) versus 1,302 (30%) h*ng/mL. These results indicate that ORH-2014 at 15 mg is safe, bioavailable, and provides the required arsenic exposure compared to intravenous arsenic trioxide at the approved dose (0.15 mg/kg); this ORH-2014 dose is recommended for future trials. (NCT03048344; www.clin-icaltrials.gov).

Development of clinical dosage forms for a poorly water-soluble drug II: formulation and characterization of a novel solid microemulsion preconcentrate system for oral delivery of a poorly water-soluble drug.

The solution of a poorly water-soluble drug in a liquid lipid-surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. The drug (aqueous solubility: 0.17 microg/mL at pH 1-8 and 25 degrees C) was dissolved in a melt of the mixture at 65-70 degrees C and then the hot solution was filled into hard gelatin capsules; the liquid gradually solidified upon cooling below 55 degrees C. The solid system was characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), confocal Raman microscopy (CRM), and the dispersion testing in water. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55-60 degrees C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of self-microemulsification.

Measurement of surface pH of pharmaceutical solids: a critical evaluation of indicator dye-sorption method and its comparison with slurry pH method.

Two methods for the measurement of surface pH of pharmaceutical solids, namely, the dye-sorption method and the slurry pH method, were compared. High purity drug substances, instead of excipients, were used as model solids, because acidic or basic impurities present in excipients could influence slurry pH. Solid test samples were prepared by sorption of methanol-water solutions of several indicator dyes, and their diffuse reflectance UV-visible spectra were measured. The solid surface pH values were estimated by comparing base-to-acid peak ratios of the diffuse reflectance UV-visible spectra of solid samples to the calibration plots of dye solutions in aqueous standard buffers of known pH. In the slurry pH method, pH values of concentrated slurries of the compounds in water were considered to represent solid surface pH. The agreement between the two methods was mixed and depended on the compound or the indicator used. It was concluded that in many cases calibration plots of indicator dye spectra in aqueous buffers were not applicable to the solid state, and, as a result, the reliability of the method was low. The slurry method provided a simple and reliable measurement of surface pH indicating that concentrated slurry may closely represent solid surface pH.

Trends in solubility of polymorphs.

Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on solubility or dissolution of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on solubility? A large number of literature reports on solubility or dissolution of polymorphs were reviewed and the data were analyzed for trends in solubility ratio of polymorphs. The general trend reveals that the ratio of polymorph solubility is typically less than 2, although occasionally higher ratios can be observed. A similar trend is also observed for anhydrate/hydrate solubility ratios, although anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to estimate the ratio of solubilities of polymorphs from thermal data. The trend in estimated solubility ratio shows good agreement with the one observed with experimentally determined solubility values.