Engineered particles demonstrate improved flow properties at elevated drug loadings for direct compression manufacturing.

Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D50=24µm) and particle engineered wet milled API (D50=70µm and 90µm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ffc<4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ffc>10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized.

Oxidative degradation studies of an oxazolidinone-derived antibacterial agent, RWJ416457, in aqueous solutions.

The rates of oxidative degradation of a new antibacterial drug, RWJ416457, in aqueous solutions were investigated over the pH-range of 2 to 10. Two oxidative degradates were identified and the influences of pH, buffer concentration, metal ions, metal chelating agents, and temperatures were studied. The pH, metal chelating agents, and metal ions significantly changed the product distribution in addition to the degradation rate. Oxidative degradation is believed to follow a hydrogen abstraction (HAT) pathway. One degradate was the major product under acidic conditions and its predominance is attributed to a resonance-stabilized intermediate. The importance of the resonance structure was diminished under neutral and basic conditions. The product distribution changed and two degradates were formed in equal amounts. The study results guided the formulation development to minimize oxidation.

Parenteral formulation and thermal degradation pathways of a potent rebeccamycin based indolocarbazole topoisomerase I inhibitor.

The development of a practical and pharmaceutically acceptable parenteral dosage form of 1 is described. A cosolvent formulation strategy was selected to achieve the necessary human dose of 1 for administration via intravenous infusion. The final market formulation of 1 chosen for commercial development and Phase II clinical supplies was the topoisomerase inhibitor dissolved in a 50% aqueous propylene glycol solution vehicle with 50mM citrate buffered to pH 4. The thermal degradation pathways of 1 in this aqueous propylene glycol vehicle in the pH range of 3-5 were determined by relative kinetics and degradation product identification using LC/MS, LC/MS/MS, and NMR analysis. The primary mode of degradation of 1 in this aqueous cosolvent formulation is hydrolysis affording the anhydride 2 (in equilibrium with the dicarboxylic acid 3) and release of the hydrazine diol side chain 11. Subsequent oxidative degradation of 11 occurs in several chemical steps which yield a complicated mixture of secondary reaction products that have been structurally identified.

Mechanism of hydrolysis of a novel indolocarbazole topoisomerase I inhibitor.

The degradation kinetics and reaction product profile of the antitumor agent 1 in aqueous solution was studied. Hydrolysis of the pendant imide ring of 1 is the primary mode of thermal degradation in aqueous solution, and the pH rate profile of 1 has a V-shape indicating that hydrolysis of the imide ring can be catalyzed by either acid or base. Hydrolysis of 1 to the anhydride derivative 3 or the dicarboxylic acid derivative 4 is stepwise and the intermediates 2a and 2b formed by initial hydrolytic attack have been observed under alkaline conditions. An overall mechanism for the hydrolysis of 1 in aqueous solution has been proposed. Extrapolating Arrhenius behavior to the hydrolysis reaction of 1 in aqueous solution maintained at a pH value of 4 suggests an aqueous buffered formulation has sufficient thermal stability to be considered a robust room temperature drug product.

Design of an i.v. formulation of an unstable prodrug candidate for prostate cancer treatment: solution chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin.

The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log k(obsd) on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described.

Assessing aggregation of peptide conjugate of doxorubicin using quasi-elastic light scattering and 600 MHz NMR.

The use of doxorubicin in treating prostate cancer is limited by its systemic toxicities especially cardiotoxicity and immunosuppression. Prodrugs that reduce the systemic exposure of doxorubicin are believed to provide a safety advantage. A prodrug of doxorubicin which contains a peptide sequence that can be recognized by prostate-specific antigen (PSA) and cleaved in the prostate was formulated for clinical use. The i.v. formulation and manufacture of this peptide conjugate posed several challenges. The main issue of the i.v. formulation were chemical and physical stability. The physical stability challenges posed during formulation and manufacture of his peptide conjugate is described herein. A heptapeptide conjugate of doxorubicin was found to aggregate in solution forming large ill defined aggregates (60-1300 nm). In contrast to doxorubicin, the average hydrodynamic diameter measured for this compound by dynamic laser light scattering technique is very large. Increasing concentration of the drug and lowering pH promoted aggregation. We rationalize the difference in the effective hydrodynamic diameter due to hydrogen bonding of the peptide which allows for the formation of large particle sizes relative to doxorubicin. We have also used 600 MHz 1H NMR to assess the aggregation of this compound.