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Aspects for Developing and Processing Solid Forms

Michael Gruss

Dr. Michael Gruß - Solid State Concepts, Hermannstr. 8, 5062 Aachen, Germany

1.1 Aspects for Developing and Processing Solid Forms

1.1.1 Introduction

Due to progressing through time and space, we constantly learn and forget. We lose things out of sight and focus on the ones that are of most importance and interest. Consequently, we cannot keep pace on every single field of technology and science. Career pathways are manifold. It is fairly natural that people in management positions who take over the responsibility to direct companies, departments, or groups cannot be experts in all the domains falling under their responsibility. Therefore, they have to educate themselves and rely on their staff, employees, team members, suppliers, contract organizations and consultants, and the assessments delivered. Decisions are made on such a base. Those decisions determine the commercial fate of the business, which in turn determines the well-being of those who gave input into the decisions. A circle of life? Will just the fittest survive?

1.1.2 Education and Personal Background

Some lack of knowledge and understanding of impact and relations may occur especially in fields that are typically not in the focus of a general chemical, medicinal, or pharmaceutical curriculum. Organic compounds constitute the majority of active pharmaceutical ingredients (API) very often in the form of crystalline solids. Nevertheless, solid-state-related topics for organic compounds are treated in introductory organic synthetic textbooks, like the Organikum [1], just on a few pages that do not go much into the details. Crystallization (including selection of the solvent, recrystallization, and crystallization from the melt) is explained in two pages, and structure analysis by means of X-ray is mentioned in another page.

Besides, still a predominant perception of solid-state characterization techniques, in particular X-ray powder diffraction (XRPD), is that the investigations are expensive. Admittedly, XRPD is not as widely distributed and readily accessible as spectroscopic and chromatographic techniques. Consequently, solid compounds and dosage forms are primarily characterized by the analytical techniques that are easily available. It is perfect to assess purity profiles and determine the solubility and dissolution profiles. Unfortunately, it is not sufficient to analyze the liquid state because that does not reveal much about the properties of the material in the solid state. Additional processing knowledge is also needed to design and modify solid-state properties.

Our current position, our educational background, as well as the social and technical environment that surrounds us determine the perception of threads and opportunities.

As long as during chemical development or production, solid-state-caused obstacles can be overcome by some, maybe magic and not really understood, measures that everything is fine or, more precisely, appears to be fine, at least for the moment. No further resources, time, and money are invested to understand the cause-effect relations. How long will this satisfaction for saving money last? Who is eventually paying the bill for lack of thoroughly understanding the processes and interdependencies? The advice is to implement solid-state experts into CMC or other development and processing teams. Taking the advantage and benefit from the different perspective, they can add to discussions and innovations.

In the past 20-30 years, solid-state development became more and more important in the pharmaceutical industry. Many treatises in print and online cover a broad variety of aspects that can be subsumed under the roof of solid-state development. This concerns not just molecules that are API but also many other compounds classified as fine chemicals, agrochemicals, explosives, or those having a relevance for nutrition products. The eye-catching word is mainly "polymorphism" that, along with similar terms like "polymorph" and "pseudo-polymorph" or terms often discussed in the context like "hydrate", "solvate", "salt", "cocrystal", "co-crystal", or "amorphous", was and still is worthwhile to cause attention.

The attention culminated to a hype that has today become a scientific and commercial important field of sound investigation to ensure proper development and subsequent successful marketability of products in general. However, in the world of pharmaceuticals, the interest is beyond commercial aspects related to ensuring safety and efficacy of the products dedicated to reduce suffering from diseases or curing patients.

Consequently, many stakeholders are involved in solid-state research, development, manufacturing, and commercialization. But it is also the other way round. Chemists and pharmacists who are active in the field of development and processing of solid compounds have lots of interfaces to other departments from which they get or to whom they deliver information and materials as exemplified for a crystallization laboratory in Figure 1.1.

Figure 1.1 The crystallization laboratory - integrated in pharmaceutical development and manufacturing.

Obviously, every single discipline can consider itself as the most important and thus justifies its position in the center of this representative arrangement. Actually, the center of Figure 1.1 only represents the point of view and maybe the self-conception. Solid-state development, particularly for pharmaceutical applications, is a complex and ever-changing setup involving and needing lots of disciplines for successfully mastering the development and manufacturing workflows.

Looking behind the scenes, stepping somewhat back from the science but without neglecting the importance of a sound understanding of the basics and the implementation of solid-state-related processes is the intention of the following chapters constituting this edition. Every chapter was contributed by someone who is an expert in his or her particular field, someone who illuminates the aspects of his or her domain with the awareness of being a part of the whole. While reading the chapters, consider its topic as standing in the center of the arrangement (Figure 1.1). Development and processing of solid compounds and forms is apparently enlightened from different perspectives. Therefore, some aspects are covered not just by one author. When there is light, then there is shadow. Not every aspect can be treated, especially because the chapters were intentionally written from a subjective standpoint and perspective. Personal preferences, experiences, and peculiarities directed the content. Other perspectives and considerations may well exist.

Solid-state development and processing is nothing that can be handled as an isolated aspect of pharmaceutical R&D or manufacturing, although a lack of general understanding of the foundations, disregarding the essential impact the solid state has on process and eventually product quality, is surprisingly still around in the industries.

This is understandable from one perspective. Dedicated experts are typically required to address the many topics showing up in the course of pharmaceutical research and particular pharmaceutical development and manufacturing. All of them are well trained and have skills in their particular sciences or businesses. Education at university is focusing on the formation of domain experts. As a drawback, less time is typically available to look to the left and to the right, forward and beyond of the own field of expertise.

As a consequence, all those experts eventually involved in versatile R&D and manufacturing teams have the duty to ensure that their colleagues (or "interfaces") also get an understanding of the impact of their particular field of expertise for the whole process and vice versa. All participants in R&D and manufacturing processes have the obligation to accentuate the need and significance of the topics addressed by themselves and their laboratories or departments. There is a necessity for people having the capability to act as coaches, teachers, and trainers; devoted to their field of expertise but not trapped therein; on the contrary, open minded and willing to share knowledge. People dedicated to draft, construct, and maintain their part of the development and production, as well as of business processes.

Getting the knowledge out of the heads. What is important to share? What should others know about your business? Besides sciences, what is also important to communicate to make industrial and commercially oriented environments work?

The intention is to cover the most essential topics in industrial, mainly pharmaceutical, environments that are related to the manifold of properties and characteristics solid compounds have.

1.1.3 Societal Impact - Fishing in Foreign Waters

The societal impact or the impact of society - human being are creating the society they live in and individuals are formed by the society they live in. Dealing with societal, economical, and historical impact on science and business is typically not a field harvested by a solid-state expert. Other...