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Integral BioSystems
Formulation Development and Manufacturing

As part of pre-formulation, we offer accelerated stability studies, as a function of pH and temperature, API lot-to-lot analysis, bulk and tap density, structural identity, excipient selection and compatibility, particle sizing, partition coefficient, photostability, pH-solubility, pka determination, polymorph screening, thermal analysis by DSC and TGA, salt form selection, solid-state stability, solution phase stability and the development of stability-indicating methods.

Based on the solubility and stability data, formulation prototypes will be prepared and optimized to be stable at pH 7.4. For example, basic formulation criteria for intravenous administration dictates that the final infused solution (or end use solution) be isotonic with body fluids. If a solution is hypotonic, cells have a high propensity to undergo hemolysis due to absorption of water. Conversely, hypertonic infused solutions have a high propensity of causing cells to collapse due to water loss. Furthermore, it is important that the pH of the infused solution be within the recommended USP guideline of being between 5 and 8. Infused solutions of pH < 3 cause pain and phlebitis, and pH > 9 cause inflammation and venous irritation. Further, the formulation vehicle must not have a buffering capacity > blood, in order to quickly adjust to physiological pH, after infusion. These parameters are optimized through multiple iterative experiments to first achieve solubility in biocompatible solvents, then to achieve thermodynamic and biological balance with body fluids. Further, the clearance parameters of the vehicle are paramount, since some excipients have been known to collect in the liver and kidneys.
The formulation criteria for each route are different. Our scientists have the experience to develop formulations that utilize excipients that are approved for use in humans. Our laboratories are well equipped to develop formulations for the intravenous, ophthalmic, transdermal and IV routes.

Analytical Method Development.
As part of formulation development, Integral BioSystems scientists develop research methods to characterize the drug formulations. These methods are developed for specificity, linearity, precision and accuracy. We develop methods that are stability-indicating, so that changes in formulations can be monitored.

Scale-Up, Tech Transfer to Manufacturing.
The selected prototype formulation will be scaled up and made appropriate for CTM manufacturing. Thus, process controls and appropriate engineering parameters to prepare a sterile parenteral formulation will be developed. These require multiple experiments that steps up to 1/10 the manufacturing scale.

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