Product and process understanding
The academic research team led by Prof Anant Paradkar at CPES is focused on developing an in-depth fundamental understanding of the influencing factors on both product and process development in the pharmaceutical and related industries. Our research themes cover crystal engineering, cocrystals, amorphous forms, polymorph stabilisation and innovative drug delivery technology. The team are experts in solving pharmaceutical and nutraceutical product and manufacturing problems and use a QbD approach to systematically understand the key aspects of process and product development.
Experts in crystal engineering
Crystal engineering is the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in design of new solids with desired physical and chemical properties. Increasingly drug development candidates suffer from low solubility and show poor and unpredictable bioavailability particularly those delivered via the oral route. Crystal engineering investigations into active pharmaceutical ingredients (API) can be an important tool in the design of solid state forms with improved dissolution rates, solubility and ultimately bioavailability. An in-depth understanding of the crystallisation processes and the molecular properties of the API is essential in the design of pharmaceutical final dosage forms.
The academic research team at CPES are focused on developing an understanding of the crystallisation process and designing novel methods for the manufacture of new forms of APIs. For example, the CPES team are leading experts in the understanding of the formation of co-crystals and have explored many different processing methods. In addition, the team have an excellent reputation in their knowledge of polymorphic transformations and processes that can be used to stabilise novel polymorphs of APIs.
Cocrystals represent a novel class of crystalline solids which consist of two or more molecular species usually held together by non-covalent bonds. Pharmaceutical cocrystal can alter the physicochemical properties of APIs to improve solubility, dissolution rate, particle characteristics and stability. Pharmaceutical co-crystals therefore possess scientiﬁc and regulatory advantages along with enormous intellectual property potential. Recently, the FDA approved the valsartan:sacubitril cocrystal Entresto as a dosage form in the treatment of heart failure. To obtain a successful pharmaceutical cocrystal product, it is crucial to understand cocrystal behaviour during manufacturing, storage, and administration as co-crystals can undergo diﬀerent types of structural changes. The research team at CPES have many years’ experience in the study of cocrystals, investigating structural vs activity relationships and novel methods of manufacture.
CPES researchers have investigated novel manufacturing methods for cocrystallisation with significant cost saving and scale-up benefits over more conventional methods, for example:
- Continuous solvent free cocrystallisation via melt extrusion
- Continuous cocrystallisation through solid state shear milling as shown in the figure opposite
- Microwave assisted cocrystallisation
- Ultrasound assisted cocrystallisation
The amorphous form and understanding stabilisation
Preparation of amorphous forms to increase dissolution rate and bioavailability of poorly water-soluble drug is now well established. Though there are many reports describing methods of preparation and application of the amorphous form, it is equally important to note that devitriﬁcation of amorphous drugs has limited their applications to a great extent.
The commercial use of such systems has been limited, primarily because of manufacturing difﬁculties and stability problems. Several attempts have been made to obtain and stabilize drugs in amorphous state.
The research team at CPES are experts in the preparation and stabilisation of amorphous forms using a range of in-house enabling technologies including hot melt extrusion, melt granulation, spray and freeze drying.
Process induced polymorphic transitions
Researchers at CPES have extensive knowledge of investigating polymorphism. Using a range of specialist analytical techniques the team characterise polymorphs of drug substance and identify transitions between metastable and thermodynamically stable forms.
Pharmaceutical processing has the potential to disrupt the crystal lattice of APIs and has thus gained considerable attention. Diﬀerent molecular arrangements can provide diverse physical and chemical properties in pharmaceutical substances, thus altering solubility, density, stability, and bioavailability. Several unit operations employed to prepare solid dosage forms, such as grinding, milling, drying, and compression may induce solid-state polymorphic transformation.
The CPES research team has explored various processes including solvent free, scalable thermo-mechanical technology for continuous crystalline transformation using a hot melt extruder.
Process understanding through QbD and PAT
Quality by Design (QbD) is a systematic approach to pharmaceutical development that refers to designing and developing formulations and manufacturing processes that can generate a prescribed product quality. In other words, QbD adopts the understanding that “quality cannot be tested into products; it should be built-in during the designing phase”
For in-depth process understanding the centre has a range of Process Analytical Technologies (PAT) including in-line NIR and Raman techniques and expertise in applying QbD approaches to process optimisation.
In addition researchers at the centre have expertise in analytical chemistry and access to an impressive range of analytical equipment that enables them to comprehensively characterize and screen both active ingredients and excipients.