Solid form changes during drug development: good, bad, and ugly case studies
© The Author(s) 2016
Received: 9 November 2015
Accepted: 17 February 2016
Published: 25 February 2016
The relevance of solid form in drug development has been well established over time. In order to fully understand drug properties, attention has been paid to solid state structure of drug molecules and their relationship to the drug formulation. While each drug developer has had their own strategies and workflows for screening and choosing solid forms of drug molecules, the industry is aware of instances where “the best laid plans” often go awry. This manuscript has summarized several case studies in development programs that display the “good, bad, and ugly” of solid form changes.
KeywordsSolid forms Crystalline forms Amorphous materials Polymorphs Salts Cocrystals Amorphous solid dispersions Case studies
It has been reported that the solid form of active pharmaceutical ingredients (APIs) has significantly impacted quality and consistency of the final dosage form for drug development compounds (Newman and Byrn 2003), especially for solid oral dosage formulations. Therefore, monitoring and controlling the API solid form in both drug substance and drug product has been recommended in order to ensure consistent biopharmaceutical properties throughout a drug development program.
Every innovator drug developer has approached API solid form decisions with a unique paradigm; however, identifying and maintaining the optimal API solid form in early pharmacokinetic studies, as well as maintaining this form through product launch, has been recognized as an ideal situation. This utopian scenario, however, has often been noted to be far removed from reality, especially if the API solid form has been ignored or assumed to be trivial for a particular program. This has often led to significant program delays and cost as bioequivalence studies, new crystallization studies, or formulation development may have been needed.
This manuscript presents the “good, bad, and ugly” aspects of API solid form changes in the pharmaceutical industry. It has explored and elaborated upon specific case studies that outline the impact of API solid form changes brought about by choosing a non-ideal salt form for early preclinical development, relaxed due-diligence for a “fast-tracked” compound, a serendipitous late stage form change, lack of attention to solid form for an in-licensed compound, and a less than bullet-proof intellectual property (IP) landscape surrounding an innovator molecule.
The goal of these examples was to show that adequate attention to API solid form during development will aid in managing risk for a program. Whether an innovator company was looking to out-license a gold molecule as a platinum package, an innovator company was looking to bring a drug to market with a strong patent landscape, or a generic company was looking to enter the market with IP for their molecule, the case studies presented in this manuscript clearly show that API solid form is an important aspect of any development program.
The case studies presented, in addition to many other un-published examples, have confirmed to pharmaceutical scientists that no screening strategy can guarantee that all crystal forms have been discovered. However, appropriate attention to API form and a sound screening strategy has had the potential to mitigate the risk for form changes in the API and drug product.
Indinavir - early salt form change
pH Stability Data for Indinavir (used with permission from Ref (Crixivan Package Insert. (available at http://www.merck.com/product/usa/pi_circulars/c/crixivan/crixivan_pi.pdf. Accessed 2 March 2015))
k1 (hr−1) at 40 °C
t1/2 (days) at 40 °C
0.1 M HCl
2.16 × 10−3
0.1 M maleate
1.14 × 10−3
0.1 M citrate
7.12 × 10−4
0.1 M citrate
3.36 × 10−4
0.1 M citrate
1.10 × 10−4
0.1 M carbonate (1/1 MeOH/H2O)
1.23 × 10−3
This example has clearly displayed the utility of identifying the appropriate salt form before clinical trials have been initiated and has also represented a “good” scenario for solid form in development. This case study has presented a classic example of solid state form impacting pharmacokinetic profiles of a drug. The example has also shown that relatively poor physicochemical properties can be mitigated with a thorough understanding of both chemical and physical stability profiles. The sulfate salt ethanolate displayed excessive hygroscopicity and form change potential; however, processing and storage conditions were identified to successfully process and store API and drug product.
DPC 961 – Form change on a fast track compound
The lessons learned from this case study would vary based on the company’s risk-management strategy. It has been generally accepted that isolating the final crystal form through desolvation would be a non-ideal process; rather, a process where the final form has been directly nucleated and grown (with or without seeds) would be preferred. However, there have been compounds that, when developed initially, have only appeared to form solvates. These solvates may or may not have had the potential to de-solvate to a physically stable anhydrous crystal form. In this case study, Form I appeared to exhibit adequate physical stability, but was not found to be an anhydrous crystal form that could have been directly nucleated and grown in an appropriate solvent system. Due to the speed of the program, it could have easily been argued that the process was robust in isolating Form I, as 29 batches had been completed without incident. The opportune discovery of Form III may have occurred due to a variety of causes including, but not limited to: impurity differences (either level or actual type of impurities) in the process stream, unique levels of supersaturation, or foreign particle providing heteronuclear templates for nucleation. It is not known whether extensive screening early in the program would have uncovered Form III. However, many compounds that have only been isolated as a solvate had often times masked an anhydrous crystal form that had been anticipating the right trigger in order to be discovered. Therefore, an appropriate and diligent level of crystal form screening should be applied to this type of compound, especially since the compound was designated at BCS II. The screening strategy should have involved conditions attempting to avoid solvate formation (Campeta et al. 2010). This “fast-track” compound could be deemed a “bad” scenario when the time delays and increased costs to the project have been added to the development plan.
Atorvastatin - crystalline form change in late development
The only known solid form for atorvastatin calcium in Phase 1 and 2 clinical trials was the amorphous form. It exhibited poor filtration and drying characteristics for large scale batches and required protection from heat, light, oxygen, and moisture (Briggs et al. 1999). During Phase 3 clinical trials, a crystalline form was produced at scale which was determined to be a trihydrate and referred to as Form I (Briggs et al. 1999). This crystalline form possessed a number of advantages over the amorphous form including higher purity, improved chemical stability, tighter uniformity in particle size distribution, and better filtration and drying properties. While finding a new form at this stage of development would normally be undesirable, the improvements gained with the new crystalline form were substantial enough for researchers to change the solid form during late development. All aspects of the project needed to be repeated, such as the API manufacturing process development, formulation development, stability studies, analytical methods, and human bioequivalence testing. Tablets produced with amorphous and crystalline trihydrate atorvastatin calcium showed a difference in the rate of absorption, but equivalent extent of absorption in the bioequivalence test (Pfizer Citizen Petition. Docket no 2005P).
Other crystalline forms were patented along with Form I (designated Forms II and IV) (Briggs et al. 1999), and additional forms followed in subsequent patent applications (Byrn et al. 2003; Tesslor et al. 2003; Van Der Schaaf et al. 2009). The next challenge for the team was to develop a crystallization process that produced uniquely Form I with the desired characteristics they needed. One patented process reported that adding methyl-t butyl ether (MTBE) to the reaction mixture after forming the salt, followed by subsequent seeding, had produced the desired Form I (Tully 2003).
The FDA orange book has listed a number of patents for atorvastatin calcium, including the composition of matter patent (expired September 24, 2009), a salt patent including the calcium salt (expired Dec 28, 2010), and the crystalline Form I patent (expires July 8, 2016). By using a form other than Form I, generic products were technically allowed on the market in 2010. After numerous legal battles and an agreement between Pfizer and Ranbaxy, the generic version of Lipitor® was available in late 2011 (Lie 2009).
The atorvastatin story has covered a number of teaching points regarding solid forms. Polymorph screens were not routinely performed when atorvastatin was under development and it was common to find forms during scale-up, especially when conditions were changed. In the case of atorvastatin, a screen was performed after the crystalline form was found and a number of forms were produced, based on the patent literature (Briggs et al. 1999; Byrn et al. 2003; Tesslor et al. 2003; Van Der Schaaf et al. 2009). In present day cases, a solid form screen should be performed in early development to find a suitable form long before Phase 3 clinical trials. An earlier solid form screen would also have prevented the repeat of major studies late in development, as seen when atorvastatin Form I was found. Screening studies do not guarantee that all forms have been found, but they have significantly reduced the risk for most programs. The patents listed in the Orange Book and the strategy of using patents to maintain market share have also been recognized as an important lesson from this example since it has necessitated consideration of a patent strategy whenever new forms (polymorphs, hydrates, solvates, salts, cocrystals, amorphous solid dispersions, etc.) have been found during development.
While the initial discovery of a crystalline form during Phase 3 clinical trials would have normally been considered a “bad” scenario, the atorvastatin story has proven that after the extra work has been completed, a very “good” scenario and a successful product resulted.
Gatifloxacin - crystalline form changes with a licensed compound
Initial clinical formulations at BMS utilized the sesquihydrate in a wet granulation process. The clinical batch failed specifications when a new crystal form was discovered in the batch. The new crystal form was confirmed as a pentahydrate (Raghaven et al. 2002), which was found to be less soluble and more stable in various formulations (wet granulations, dry blends, and aqueous suspensions). Issues with the initial clinical sesquihydrate formulation, as well as difficulty producing pure sesquihydrate material, had prompted crystallization studies to find a better understanding of the solid form landscape.
Gatifloxacin has provided an example of multiple form changes throughout mid to late stage development. These changes created significant additional work around API crystallization development, formulation processing, analytical methods, and biological studies (i.e., bridging and bioequivalence studies). This case study has also demonstrated the criticality of due diligence for in-licensed compounds, including proper screening. Companies that in-license a compound should ask specific questions about the solid form studies that were performed to determine the scope of knowledge and inter-relationships between forms, and how the solid form landscape would impact the desired dosage form and development plan. For companies that out-license a compound, a solid form study targeted toward the most stable form, crystallization conditions, and formulation processes have resulted in a much stronger package.
While the initial package for gatifloxacin seemed straightforward with only two hydrated forms, it should be classified as an “ugly” scenario due to the solid form changes and additional studies.
Olanzapine - crystalline change from free acid to salt
This case study has illustrated the advantages of using novel solid forms for innovative drug products. The change in solid form to a crystalline pamoate salt resulted in a less soluble salt, which has previously not been desired by researchers. However, in this case, the less soluble salt exhibited all the properties needed for an improved sustained release formulation. Rather than an oral dosage form, an intramuscular injection was produced to capitalize on the lower solubility. The result became a dosage form with good efficacy and superior compliance. Additionally, patent coverage around the new salt has also extended coverage for a year after the olanzapine free base expires.
Oxybutynin- crystalline change from salt to free base
This case study shows how a change in form and delivery route has not only reduced side effects, but also resulted in a more efficient and convenient drug product for the patient. The development of the patch required a change in form from the hydrochloride salt to free base, which enabled the drug to pass through the skin. Finding a different form to develop an improved drug product required an understanding of the properties needed for a particular dosage form and thorough characterization of various forms. This change in form could include a polymorph, free acid/base, salt, cocrystal, or amorphous solid dispersion. Specific counterions or guest molecules would need to be considered for certain delivery routes, such as dermal, ophthalmic, intravenous, or intramuscular formulations (Paulekuhn et al. 2007). Determining the issues with current products and finding creative solutions using form and formulation to produce an improved product has been recognized as a true “win-win” in lifecycle management.
The case studies in this manuscript have been presented to show why it has been critical to characterize, understand, and monitor the solid form in all stages of drug discovery and development. While these case studies have been presented in the literature, there have been even “uglier” cases that have not been published. It is important for researchers to realize that form selection is not a unit operation, but an integral part of the entire drug development process, with no clear beginning or end; instead, there should be continuous scrutiny and monitoring as a candidate progresses from discovery to development to market and beyond.
active pharmaceutical ingredient
Biopharmaceutics Classification System
Biopharmaceutics Drug Disposition Classification System
Clinical Research Unit
Food and Drug Administration
human immunodeficiency virus type 1
long acting injection
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