Multicomponent Solid Forms: A New Boost to Pharmaceuticals

Multicomponent Solid Forms: A New Boost to Pharmaceuticals

Rahul B. Chavan (NIPER Hyderabad, India), Balvant Yadav (NIPER Hyderabad, India), Anurag Lodagekar (NIPER Hyderabad, India) and Nalini R. Shastri (NIPER Hyderabad, India)
DOI: 10.4018/978-1-5225-4781-5.ch010


Multicomponent systems provide the option of combining drugs at the supramolecular level. Among these, co-crystals have gained a widespread interest in pharmaceutical industry as US Food and Drug Administration (FDA) recently introduced new regulatory guidelines regarding this solid form that is anticipated to expand patent portfolios. Apart from co-crystals, other multi-component adducts such as co-amorphous system and eutectics are also a topic of interest for pharmaceutical researchers as they provide therapeutic advantages along with improved the aqueous solubility, dissolution, and bioavailability of poorly soluble drugs. This chapter provides a brief overview of multicomponent solid forms, their preparation methodologies, characterization, evaluation, biopharmaceutical aspects, scale up issues, and regulatory perspectives related to these solid forms. In addition, a section on future perspectives that sheds light on new therapeutic hybrids deploying drug-drug and drug-neutraceuticals combinations with improved pharmaceutical and biopharmaceutical attributes is also included.
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1. Introduction

Concurrent administration of two or more therapeutic agents which have similar or different mechanisms of action are termed as multi drug therapy and can be used to combat various ailments (Shin, Alani, Rao, Rockich, & Kwon, 2009). In comparison to single drug therapy, this approach help in targeting different key signal transduction pathways which can be more efficacious in management of diseases, since they can evade cellular resistance mechanisms. The advantages offered by multi-drug therapy are schematically depicted in Figure 1. To date, this approach has been successfully implemented for management of diseases such as HIV/AIDS, cancer, multiple sclerosis, malaria, infectious diseases, cardiovascular and metabolic diseases, hypertension, auto immune disorders and many psychiatric maladies (Conway, & Cohen, 2010; Thipparaboina, Chavan, Kumar, Modugula, & Shastri , 2015). Multi drug therapy when administered in fixed dose combinations (FDC) are cost-effective which help in reducing pill load without any additional risk of adverse events or drug resistance and hence improve the patient compliance. FDC also facilitate the reduction of managerial and manufacturing costs by reducing the outflow related to packaging and drug prescriptions. FDC products contain simple drug–drug combinations or drug–device combinations, such as drug-eluting stents or drug-biological products for use in cancer therapy. The benefits offered by FDC are often overshadowed because of its severe disadvantages such as stability issues, and solubility differences and incompatibility between the parent drugs (Thipparaboina, Chavan, Kumar, Modugula, & Shastri , 2015). Hence, there is a need to develop alternative approach which will facilitate the development of therapeutic hybrids to counter such problems. Multicomponent solids such as cocrystals, co amorphous system (CAM) and eutectics may provide solution required for delivering the drug-drug combinations with improved benefits in terms of stability, improved solubility and dissolution when compared to FDC.

Clinical success of Novartis product Entrestot a multi drug cocrystal which was approved in 2015 for effective management of chronic heart pain, is comprised of monosodium sacubitril, disodium valsartan and water, and has given a boost to pharmaceutical industry to improve the pharmaceutical attributes using multi component systems. However, developments of such multi component solid system need careful attention as it require supportive evidence on its pharmacological action and safety such as synergistic or additive effect of two drugs in addition to stability and formulation related attributes. This book chapter aims to provide a brief overview on multi component solid forms (cocrystals, co amorphous system, eutectics) and furnish information ranging from preparation, characterization, scale up and regulatory concerns related to these systems.

Figure 1.

Advantages offered by multi drug therapy: MDR- multi drug resistance


2. Multi Drug Cocrystals

As per FDA, co-crystals are dissociable multicomponent solid crystalline supramolecular complexes which contain two or more components within the same crystal lattice where in the components are in neutral state and interact via nonionic interactions’ (Aitipamula, Banerjee, Bansal, Biradha, Cheney, Choudhury, . . . Duggirala, 2012). First report on cocrystal came in 1844 for quinhydrone complex by Wholer, which was later found to be a 1:1 co-crystal of quinone and hydroquinone (Nangia, 2010). In 1995, Gautam Desiraju introduced the concept of the supramolecular synthon, or hydrogen bonded building units in crystal structures with leads from the field of supramolecular chemistry and crystal engineering (Desiraju, 1995). This concept led to a spurt of research that was responsible for the extensive growth in the field of cocrystals.

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