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Editorial
Journal of Pharmacy And Pharmacology
Selection of solid-state forms: challenges, opportunities, lessons learned and adventures from recent years Christoph Saal Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany
Correspondence Christoph Saal, SO-A - Analytical Biochemistry, Merck KGaA, Frankfurter Strasse 250, Darmstadt 64293, Germany. E-mail: [email protected] doi: 10.1111/jphp.12435
Selection of the solid-state form of an active pharmaceutical ingredient (API) has become a crucial step during pharmaceutical research and development. This can be easily recognized from the number of publications dealing with solidstate forms, in the pharmaceutical arena, which increased steadily over the last two decades. Accordingly one might ask why this has been the case, especially since the mid1990s. For example, polymorphism is known by every student occurring with classical examples such as graphite and diamond, different polymorphs of phosphor or titanium dioxide. The fundamental statement by McCrone that ‘the number of forms known for a given compound is proportional to the time and energy spent in research on that compound’ has been made in 1965.[1] However, even if this dilemma is known for half a century, there is still no unique and 100% safe way how to select polymorphs without risks and surprises. Surprises – such as for example disappearing polymorphs,[2] or polymorphs that suddenly appear – have been discussed in literature. Surprises did not only come from the academic world, but also from industry, where they lead to practical challenges. The famous Ritonavir case[3] represents just one example. Further examples from industry exist – either published[4,5] or non-published – and many companies doing pharmaceutical research and development of new chemical entities will have encountered adventures with polymorphism. From this perspective, the challenge mainly is given by the fact that metastable forms might convert to the thermodynamically stable form, and this might not be controlled, or the thermodynamically stable form might not even be known. However, during the last decades, the situation became still more challenging as pharmaceutical research compounds and development candidates became less soluble. This triggered the need to develop solid-state forms with increased bioavailability, solubility and dissolution rate, in other words a development away from the thermodynami-
cally safe ground. The principle behind this is very simple: moving up in free enthalpy will lead to higher solubility of a solid-state form. However, moving higher always bears the risk of suddenly falling down. Moreover, this has become exactly the challenge that the pharmaceutical industry is facing now for more than two decades: how to develop solid-state forms with increased free enthalpy – which by definition cannot be thermodynamically stable – but are kinetically stable, avoiding the risk of falling down and converting to thermodynamically stable solid-state forms. Salt selection, the classical tool to improve solid-sate properties, has been described a long time ago. However, even if the principles are known for a century, it can be seen that the real potential of this tool have only been brought into place during the last decades, whereas hydrochloride salts have been more or less the unique solution for salt selection until the mid-1990s, during the new millennium where diversity of salts used in new APIs increased.[6] The reason behind is obvious: As more challenging research compounds exhibiting lower solubility have been encountered, Biopharmaceutical Classification System BCS class II compounds becoming more a standard situation, selection of chloride salts did not ‘solve’ each and any problem. Further on, one has to remember that solubility and dissolution rate are not the only challenges to tackle: Further properties such as hygroscopic behaviour, particle habit, polymorphism of the salt, chemical stability, physical stability, manufacturability, processability, use of solvents, yield from manufacturing process and others also have to be addressed at the same time. As consequence, salt selection became a very individual process, specific for each new chemical entity entering clinical development. Beyond individual assessment of salt forms for research compounds, certain principles have been discovered. For example, it was realized that sulphonate salts exhibit higher solubility compared with other salt forms in many cases,[7] even if the
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 755–756
755
Selection of solid-state forms
Christoph Saal
reason behind it is not fully understood. Other approaches for salt selection, such as use of weakly coordinating anions, have been proposed.[8] Here, underlying physics to improve solubility is obvious. However, challenges such as assessing toxicological properties have still not been solved. This represents one example that bringing new concepts into drugs on the market is a long way to go. On the other hand, even if ways to implement new tools for solid-state selection into new drugs are long, it does not mean that the goal cannot be reached, or that these tools are not worth exploring. As a recent example, Ipragliflozin L-proline has been approved in Japan as the first co-crystal worldwide.[9] As co-crystals became a hot topic for solidstate form selection not more than 15 years ago, this can be regarded as real, fast progression of this concept into an approved drug. Discussion on co-crystals also has drawn much attention to the regulatory environment of solid-state selection.[10,11] The need for this debate came from the fact that a new tool for solid-state selection – co-crystals – was available in the lab and pilot plant, but no regulatory guidance was available at that time. Finally, solid-state selection for drug substances is not to be addressed as an isolated topic: As the purpose of the drug substance always is to make a drug product out of it, solid-state selection is closely linked to formulation development. Low solubility of research compounds had also a huge influence on formulation development, resulting in new enabling techniques such as for example hotmelt extrudates, co-precipitates, nano-milling and selfemulsifying dispersions to name only a few. In contrast to classical standard formulations such as oral tablets containing the thermodynamically stable form of the API, these more advanced formulations also require tailored solid-
References 1. McCrone WC. Polymorphism. In: Fox D et al., eds. Physics and Chemistry of the Organic Solid State, Vol. II. New York: Interscience, 1965: 2: 725–767. 2. Dunitz JD, Bernstein J. Disappearing polymorphs. Acc Chem Res 1995; 28: 193–200. 3. Bauer J et al. An extraordinary example of confirmational polymorphism. Pharm Res 2001; 18: 859–866. 4. Dinnebier RE et al. Structural characterization of three crystalline modifications of telmisartan by single crystal and high-resolution X-ray powder diffraction. J Pharm Sci 2000; 89: 1465– 1479. 756
state properties. Accordingly, solid-state selection and formulation development became and will become even more interconnected topics. We have left the scenario, where we select a solid-state form and then think about the formulation, as the solid-state form will be a one-fits-all solution. Instead, we have to bear in mind the formulations for early clinical development versus late stage clinical development and marketing. Solid-state selection has to be based on the specific needs of these formulations. From an educational point of view, topics as discussed above require knowledge and experience about salt and polymorph screening and selection, co-crystals, in-silico predictions for solid-state forms, new tools for X-ray crystallography such as pair-distribution functions, and obtaining crystal structures from powder X-ray data, quality by design approaches for crystallization development and tailoring crystal habits. Additionally, an improved interdisciplinary understanding is required, involving functions such as medicinal chemists, preformulators, formulators, people working in analytics, drug-substance manufacturers, people dealing with pharmacokinetics, toxicologists and last but not least regulatory disciplines. This increased the need of a better understanding of complex solid-state properties, and the tools that are more versatile to design them become relevant not only for the industry, but also for the academia, as a source of innovation in this field, and regulatory authorities reviewing and approving respective drugs. With the present special issue of Journal of Pharmacy and Pharmacology, we would like to contribute to advancing solid-state selection in the pharmaceutical arena by presenting several research publications and reviews on relevant aspects of selecting solid-state forms.
5. Cimarosti Z et al. Development of drug substances as a mixture of polymorphs: studies to control form 3 in Casopitant mesylate. Org Process Res Dev 2010; 14: 1337–1346. 6. Paulekuhn S et al. Trends in active pharmaceutical ingredient salt selection based on analysis of the orange book database. J Med Chem 2007; 50: 6665–6672. 7. Elder DP et al. The utility of sulfonate salts in drug development. J Pharm Sci 2010; 99: 2948–2961. 8. Shamshina JL et al. Ionic liquids in drug discovery. Expert Opin Drug Deliv 2013; 10: 1367–1381. 9. New Drug Approvals. [Cited 5 Apr 2015]. Available from URL: http://
newdrugapprovals.org/2013/12/19/ ipragliflozin/. 10. FDA. Guidance for industry: Regulatory classification of pharmaceutical co-crystals. April 2013. 2013. [Cited 5 Apr 2015]. Available from URL: http:// www.fda.gov/downloads/Drugs/ Guidances/UCM281764.pdf. 11. EMA. Draft reflection paper on the use of co-crystals and other solid-state forms of active substances in medicinal products. July 2014. 2014. [Cited 5 April 2015]. Available from URL: http://www.ema.europa.eu/ema/ index.jsp?curl=pages/includes/ document/document_detail.jsp? webContentId=WC500170467&mid= WC0b01ac058009a3dc.
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 755–756
Copyright of Journal of Pharmacy & Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Editorial
Journal of Pharmacy And Pharmacology
Selection of solid-state forms: challenges, opportunities, lessons learned and adventures from recent years Christoph Saal Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany
Correspondence Christoph Saal, SO-A - Analytical Biochemistry, Merck KGaA, Frankfurter Strasse 250, Darmstadt 64293, Germany. E-mail: [email protected] doi: 10.1111/jphp.12435
Selection of the solid-state form of an active pharmaceutical ingredient (API) has become a crucial step during pharmaceutical research and development. This can be easily recognized from the number of publications dealing with solidstate forms, in the pharmaceutical arena, which increased steadily over the last two decades. Accordingly one might ask why this has been the case, especially since the mid1990s. For example, polymorphism is known by every student occurring with classical examples such as graphite and diamond, different polymorphs of phosphor or titanium dioxide. The fundamental statement by McCrone that ‘the number of forms known for a given compound is proportional to the time and energy spent in research on that compound’ has been made in 1965.[1] However, even if this dilemma is known for half a century, there is still no unique and 100% safe way how to select polymorphs without risks and surprises. Surprises – such as for example disappearing polymorphs,[2] or polymorphs that suddenly appear – have been discussed in literature. Surprises did not only come from the academic world, but also from industry, where they lead to practical challenges. The famous Ritonavir case[3] represents just one example. Further examples from industry exist – either published[4,5] or non-published – and many companies doing pharmaceutical research and development of new chemical entities will have encountered adventures with polymorphism. From this perspective, the challenge mainly is given by the fact that metastable forms might convert to the thermodynamically stable form, and this might not be controlled, or the thermodynamically stable form might not even be known. However, during the last decades, the situation became still more challenging as pharmaceutical research compounds and development candidates became less soluble. This triggered the need to develop solid-state forms with increased bioavailability, solubility and dissolution rate, in other words a development away from the thermodynami-
cally safe ground. The principle behind this is very simple: moving up in free enthalpy will lead to higher solubility of a solid-state form. However, moving higher always bears the risk of suddenly falling down. Moreover, this has become exactly the challenge that the pharmaceutical industry is facing now for more than two decades: how to develop solid-state forms with increased free enthalpy – which by definition cannot be thermodynamically stable – but are kinetically stable, avoiding the risk of falling down and converting to thermodynamically stable solid-state forms. Salt selection, the classical tool to improve solid-sate properties, has been described a long time ago. However, even if the principles are known for a century, it can be seen that the real potential of this tool have only been brought into place during the last decades, whereas hydrochloride salts have been more or less the unique solution for salt selection until the mid-1990s, during the new millennium where diversity of salts used in new APIs increased.[6] The reason behind is obvious: As more challenging research compounds exhibiting lower solubility have been encountered, Biopharmaceutical Classification System BCS class II compounds becoming more a standard situation, selection of chloride salts did not ‘solve’ each and any problem. Further on, one has to remember that solubility and dissolution rate are not the only challenges to tackle: Further properties such as hygroscopic behaviour, particle habit, polymorphism of the salt, chemical stability, physical stability, manufacturability, processability, use of solvents, yield from manufacturing process and others also have to be addressed at the same time. As consequence, salt selection became a very individual process, specific for each new chemical entity entering clinical development. Beyond individual assessment of salt forms for research compounds, certain principles have been discovered. For example, it was realized that sulphonate salts exhibit higher solubility compared with other salt forms in many cases,[7] even if the
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 755–756
755
Selection of solid-state forms
Christoph Saal
reason behind it is not fully understood. Other approaches for salt selection, such as use of weakly coordinating anions, have been proposed.[8] Here, underlying physics to improve solubility is obvious. However, challenges such as assessing toxicological properties have still not been solved. This represents one example that bringing new concepts into drugs on the market is a long way to go. On the other hand, even if ways to implement new tools for solid-state selection into new drugs are long, it does not mean that the goal cannot be reached, or that these tools are not worth exploring. As a recent example, Ipragliflozin L-proline has been approved in Japan as the first co-crystal worldwide.[9] As co-crystals became a hot topic for solidstate form selection not more than 15 years ago, this can be regarded as real, fast progression of this concept into an approved drug. Discussion on co-crystals also has drawn much attention to the regulatory environment of solid-state selection.[10,11] The need for this debate came from the fact that a new tool for solid-state selection – co-crystals – was available in the lab and pilot plant, but no regulatory guidance was available at that time. Finally, solid-state selection for drug substances is not to be addressed as an isolated topic: As the purpose of the drug substance always is to make a drug product out of it, solid-state selection is closely linked to formulation development. Low solubility of research compounds had also a huge influence on formulation development, resulting in new enabling techniques such as for example hotmelt extrudates, co-precipitates, nano-milling and selfemulsifying dispersions to name only a few. In contrast to classical standard formulations such as oral tablets containing the thermodynamically stable form of the API, these more advanced formulations also require tailored solid-
References 1. McCrone WC. Polymorphism. In: Fox D et al., eds. Physics and Chemistry of the Organic Solid State, Vol. II. New York: Interscience, 1965: 2: 725–767. 2. Dunitz JD, Bernstein J. Disappearing polymorphs. Acc Chem Res 1995; 28: 193–200. 3. Bauer J et al. An extraordinary example of confirmational polymorphism. Pharm Res 2001; 18: 859–866. 4. Dinnebier RE et al. Structural characterization of three crystalline modifications of telmisartan by single crystal and high-resolution X-ray powder diffraction. J Pharm Sci 2000; 89: 1465– 1479. 756
state properties. Accordingly, solid-state selection and formulation development became and will become even more interconnected topics. We have left the scenario, where we select a solid-state form and then think about the formulation, as the solid-state form will be a one-fits-all solution. Instead, we have to bear in mind the formulations for early clinical development versus late stage clinical development and marketing. Solid-state selection has to be based on the specific needs of these formulations. From an educational point of view, topics as discussed above require knowledge and experience about salt and polymorph screening and selection, co-crystals, in-silico predictions for solid-state forms, new tools for X-ray crystallography such as pair-distribution functions, and obtaining crystal structures from powder X-ray data, quality by design approaches for crystallization development and tailoring crystal habits. Additionally, an improved interdisciplinary understanding is required, involving functions such as medicinal chemists, preformulators, formulators, people working in analytics, drug-substance manufacturers, people dealing with pharmacokinetics, toxicologists and last but not least regulatory disciplines. This increased the need of a better understanding of complex solid-state properties, and the tools that are more versatile to design them become relevant not only for the industry, but also for the academia, as a source of innovation in this field, and regulatory authorities reviewing and approving respective drugs. With the present special issue of Journal of Pharmacy and Pharmacology, we would like to contribute to advancing solid-state selection in the pharmaceutical arena by presenting several research publications and reviews on relevant aspects of selecting solid-state forms.
5. Cimarosti Z et al. Development of drug substances as a mixture of polymorphs: studies to control form 3 in Casopitant mesylate. Org Process Res Dev 2010; 14: 1337–1346. 6. Paulekuhn S et al. Trends in active pharmaceutical ingredient salt selection based on analysis of the orange book database. J Med Chem 2007; 50: 6665–6672. 7. Elder DP et al. The utility of sulfonate salts in drug development. J Pharm Sci 2010; 99: 2948–2961. 8. Shamshina JL et al. Ionic liquids in drug discovery. Expert Opin Drug Deliv 2013; 10: 1367–1381. 9. New Drug Approvals. [Cited 5 Apr 2015]. Available from URL: http://
newdrugapprovals.org/2013/12/19/ ipragliflozin/. 10. FDA. Guidance for industry: Regulatory classification of pharmaceutical co-crystals. April 2013. 2013. [Cited 5 Apr 2015]. Available from URL: http:// www.fda.gov/downloads/Drugs/ Guidances/UCM281764.pdf. 11. EMA. Draft reflection paper on the use of co-crystals and other solid-state forms of active substances in medicinal products. July 2014. 2014. [Cited 5 April 2015]. Available from URL: http://www.ema.europa.eu/ema/ index.jsp?curl=pages/includes/ document/document_detail.jsp? webContentId=WC500170467&mid= WC0b01ac058009a3dc.
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 755–756
Copyright of Journal of Pharmacy & Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
