A novel co-processing method to manufacture an API for extended release formulation via formation of agglomerates of active ingredient and hydroxypropyl methylcellulose during crystallization.

A novel process for generating agglomerates of active pharmaceutical ingredient (API) and polymer by swelling the polymer in a water/organic mixture has been developed to address formulation issues resulting from a water sensitive, high drug load API with poor powder properties. Initially, the API is dissolved in water, following which hydroxypropyl methylcellulose (HPMC) is added, resulting in the imbibing of water, along with the dissolved API, into the HPMC matrix. The addition of acetone and isopropyl acetate (anti-solvents) then causes the API to crystallize inside and on the surface of HPMC agglomerates. The process was scaled up to 20 kg scale. The agglomerates of API and HPMC generated by this process are ∼350 µm diameter, robust, and have significantly better flow than the API as measured by Erweka flow testing. These agglomerates exhibit improved bulk density, acceptable chemical stability, and high compressibility. The agglomerates process well through roller compaction and tableting, with no flow or sticking issues. This process is potentially adaptable to other APIs with similar attributes.

Biotechnology Based Process for Production of a Disulfide-Bridged Peptide.

A disulfide-bridged peptide drug development candidate contained two oligopeptide chains with 11 and 12 natural amino acids joined by a disulfide bond at the N-terminal end. An efficient biotechnology based process for the production of the disulfide-bridged peptide was developed. Initially, the two individual oligopeptide chains were prepared separately by designing different fusion proteins and expressing them in recombinant E. coli. Enzymatic or chemical cleavage of the two fusion proteins provided the two individual oligopeptide chains which could be conjugated via disulfide bond by conventional chemical reaction to the disulfide-bridged peptide. A novel heterodimeric system to bring the two oligopeptide chains closer and induce disulfide bond formation was designed by taking advantage of the self-assembly of a leucine zipper system. The heterodimeric approach involved designing fusion proteins with the acidic and basic components of the leucine zipper, additional amino acids to optimize interaction between the individual chains, specific cleavage sites, specific tag to ensure separation, and two individual oligopeptide chains. Computer modeling was used to identify the nature and number of amino acid residue to be inserted between the leucine zipper and oligopeptides for optimum interaction. Cloning and expression in rec E. coli, fermentation, followed by cell disruption resulted in the formation of heterodimeric protein with the interchain disulfide bond. Separation of the desired heterodimeric protein, followed by specific cleavage at methionine by cyanogen bromide provided the disulfide-bridged peptide.

A new perspective on the mechanical evaluation of granular material.

The mechanical strength of granules is an important parameter to be determined prior to any further downstream formulation processing. It is important to have a good gauge on the granule integrity to forecast any foreseeable powder issues associated with the material processability such as segregation, content uniformity, and material flow-ability. In this study, a systematic methodology has been developed to quantify the integrity of these granules subjected to a low frequency acoustic field to arrive at the Granule Integrity (GI) index. This methodology has been compared to existing well-established bulk characterization techniques reported in the literature such as Heckel analysis, Kawakita analysis, and Young's modulus for four different processed samples. Heckel analysis is more amenable to examine the material deformability while Kawakita analysis is better suited to understand the mechanics of granular material. Individual granule strength measurements to determine Young's modulus often show large variations across the bulk sample. The GI index in conjunction with the Kawakita analysis provides us with more mechanistic insight and understanding into the formation of these granules from a processing perspective. This paper shows the benefits of using the GI index as a practical and direct methodology to characterize the GI of bulk samples in an industrial setting.