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Driving innovation in pharmaceuticals: integrated studies of physical dissolution properties of crystalline and amorphous forms using enhanced orthogonal monitoring techniques

Periodic Reporting for period 2 - CRYDIS (Driving innovation in pharmaceuticals: integrated studies of physical dissolution properties of crystalline and amorphous forms using enhanced orthogonal monitoring techniques)

Reporting period: 2017-01-01 to 2018-12-31

The CRYDIS exchange programme will establish and support international and inter-sectoral transfer of knowledge and expertise in pharmaceutical and instrument science between several EU research institutes and industrial companies.
CRYDIS undertakes innovative, collaborative research on the clinically-important topic of dissolution of drug substance particles in bio-relevant media and the undesired subsequent nucleation and re-precipitation of the drug prior to its absorption.
Using innovative advances in UV imaging technology, CRYDIS investigates the utility of novel dissolution assays as key tools to obtain fundamental data on the mechanism and kinetics of undesired nucleation and re-precipitation during or following dissolution, a significant problem for the pharmaceutical industry which struggles to obtain sufficient exposure to poorly soluble drug substances to ensure an effective dose is absorbed by the patient.
The key technologies in this proposal offer a step change in capability and functionality, offering the potential to undertake more detailed studies of the dissolution/re-precipitation processes relevant to pharmaceutical materials. Access to this key technology and the further development of its capability offers the potential for breakthroughs in development of process understanding and of robust and widely applicable protocols, thus, contributing to faster translation of molecules to medicines to patients.
Developing and combining techniques:
High information content analytical methods for assessing drug dissolution and precipitation using UV imaging and orthogonal techniques have been developed.
A robust, simultaneous UV imaging and Raman spectroscopy approach have been established for visualizing the dissolution process and monitoring solid form changes occurring during dissolution. A step-by-step guideline for dissolution imaging studies with in situ Raman spectroscopy was developed.
An approach for local pH measurements in the immediate vicinity of the drug solid surface (in situ pH imaging) has been established using the UV-Vis imaging platform that demonstrates potential for assessment of pH changes.
Proof-of-concept studies demonstrated the feasibility of measuring drug supersaturation, precipitation and dissolution using UV-Vis imaging in combination with light microscopy and Raman spectroscopy.
Recent advances in UV-Vis imaging instrumentation facilitating dual-wavelength imaging have been utilized in development of methods for characterization of multi-component systems, e.g. drug excipient mixtures.
An interlab study using the first generation SDI system for assessing intrinsic dissolution rates of 6 drug substances addressed the extent of variability associated with the method upon development of a common protocol. Overall, the rank ordering was as expected and the variability associated with the measurements was related to the solubility of the compounds.

Studying the dissolution and precipitation of pharmaceutical materials:
The novel analytical capabilities within UV imaging/surface dissolution imaging have been exploited to conduct detailed dissolution characterization of drug substances subject to form transformation, including anhydrate to hydrate conversion and salt disproportionation.
The suitability of UV-Vis imaging for characterization of multicomponent systems, such as cocrystals and drug-polymer matrixes has been demonstrated.
In situ UV metric assays have been used to assess the performance of cocrystals.
Whole tablet imaging utilizing the Sirius SDi2 UV-Vis imaging platform has shown the potential with respect to identifying dissolution and precipitation phenomena for whole dosage forms under biorelevant conditions.

Fundamentals of nucleation processes relevant to dissolution phenomena:
Controlled supersaturation and precipitation experiments have been undertaken for assessment for induction times and precipitation rates in relation to the degree of supersaturation.
One focus is on the translation of nucleation models in bio-relevant media. To this end, the role of the components of the intestinal fluids in inhibiting nucleation and drug precipitation has been investigated and components responsible for both the inhibition and the promotion of nucleation have been identified.
CRYDIS strives to generate new knowledge on the dissolution of drug substance particles in bio-relevant media and the undesired subsequent nucleation and re-precipitation of the drug prior to its absorption.
The new insights into drug dissolution and (re-)precipitation processes are likely to facilitate the development of new, more effective products and instrumentation leading to increased competiveness for the European industry.
Knowledge obtained through CRYDIS will help enable rapid translation of molecules to medicines to patients in the pharmaceutical sector.
CRYDIS aims to foster understanding of market pull and industrial needs, processes and culture by academic secondees; to foster understanding of the opportunities for the adoption of academic research by industrial secondees; and to embed improved process knowledge within the value chain of the industry participants through inter-sectoral staff exchanges.
Dissolution imaging of sodium diclofenac