Polymorphism: A Major Risk That Pharma Companies Must Mitigate
The assessment of the potential solid forms for a candidate active pharmaceutical ingredient (API) is a vital step to identify the optimal form during the development of a drug.
Still, polymorphism remains a major risk that pharma companies must understand and mitigate, as no universal method can prove which is the best solid form with absolute confidence.
In this blog, we highlight key elements of solid form screening, from origins to challenges, and report recent discoveries in the solid form landscape of the well-known antiviral drug Ritonavir.
Why Are We Concerned About Solid Forms?
Research shows that about 85% of the marketed drugs have more than one crystalline forms. [1], [2] But why is this value concerning?
The term polymorphism refers to the ability of a compound to crystallize as more than one distinct crystal species. [3], [4] These species usually exhibit different physical and physicochemical properties that are relevant for pharmaceuticals, such as solubility, dissolution rate, and stability. [5] Solid form screening helps identify the form that provides physical and chemical stability, and which enables a bioavailable drug product to be robustly manufactured with a suitable shelf life.
Identifying and characterizing as many as possible potential solid forms of a candidate API at an early stage of development is essential to avoid:
- The potential to bring to the market unstable or non-optimal drugs that can be ineffective;
- Wasting time and money developing a drug later found to be unstable.
The well-known case of Ritonavir highlights the fundamental role of solid forms in the development and marketing of a new drug.
Ritonavir: Form III Found, 24 Years After Form II Was Discovered
The antiviral drug Ritonavir was developed at Abbott Laboratories in late 1992 and marketed in 1996. [6] The drug, used for the treatment of Acquired Immunodeficiency Syndrome (AIDS), was available as Norvir oral liquid and Norvir semi-solid capsules. [7] Both the formulations contained Ritonavir in ethanol/water based solutions, and only one crystal form was identified during the development, Form I. [7]

Two years after Ritonavir was marketed, a more stable polymorph with a much lower solubility, Form II, started precipitating out of the semi-solid formulated product. [6] An immediate reformulation of the Norvir semi-solid capsules was needed, leading to its temporary withdrawal from the market. This had a devastating impact for patients that were relying on the drug, as its withdrawal seriously threatened the supply of this life saving treatment. [7] It is estimated that Abbott lost more than US$250 million for this incident. [8]
Since this occurrence, a lot has been done to maximize the understanding of a solid form landscape, and to discover and characterize all the crystal forms that are potentially available for a drug candidate.
Nonetheless, 24 years after the appearance of Form II of Ritonavir, scientists at AbbVie Inc. serendipitously discovered a new polymorph while studying the crystal nucleation of amorphous Ritonavir, and obtained the new Form III via melt crystallization. [9]
So, how many solid forms are still unknown?
Minimization of Risks in Solid Form Development
The withdrawal of Ritonavir from the market changed the mindset of the pharmaceutical industry, which rapidly realized how important it is to identify and characterize the different solid forms of a candidate API.
Still, despite the guidance for polymorphic forms from the FDA, [10], [11, decision tree 4] every drug candidate is unique and there is no method that can provide absolute confidence that the ideal solid form has been obtained, or that all the potential solid forms have been identified. We saw this with the incident of Ritonavir and with the recent discovery of its new polymorph.
To minimize the risks associated with the stability, efficacy, and solubility of an API, a targeted solid form screening is required at different stages of the drug development.
The solid form screening is usually performed twice during the development of a drug: in the preclinical stage, to select the solid form that can proceed to clinical trials, and in the clinical stage. It aims to screen for free forms of the candidate API, its hydrates, solvates, and potential salts and/or cocrystals, to fully characterize the solid form landscape of the API, and to look for more optimal forms, including alternative salts.
Challenges and Recent Trends
The challenges that scientists encounter in solid form selection are multiple. A very recent publication analyses some of these and looks at the current trends in the solid form landscape.
The researchers at Pharmaron performed solid form screenings for 476 new chemical entities (NCEs) studied between 2016 and 2023. These covered a variety of therapeutic areas from 250 biotech and large pharmaceutical companies. [12]
A total of 425 polymorph screens were run for free forms and salts, leading to the identification of 2102 crystal forms. The survey showed that an average of 5.5 crystal forms were found for the free forms, and 3.7 for salts, demonstrating the prevalence of polymorphs for pharmaceutical compounds. [12]
Additionally, the survey identified an increasing structural complexity and molecular weight of NCEs in recent years, which often means that it is more difficult to crystallize these compounds, or to obtain good quality forms for development. [12]
Conclusions
Polymorphism is a major risk that pharma companies must understand and mitigate, as challenges in crystallization and selection of solid forms are evolving in time and are not always predictable.
Despite not being an exact science, a workflow that includes screening methodologies targeted to the candidate API supports its progress to more advanced phases of development.
Beside reducing the costs, an efficient screening helps identify the best solid form for efficiency and stability, reduces the risks of the appearance of other forms in later stages, and informs the drug development steps.
Next Steps
- Join our webinar on 13th February 2025 where Shubham Sharma, a computational materials scientist at Pfizer, will describe methods for solid form screening they used in a recent project. Follow the link to register.
- Find here additional articles on solid form screening: Development of a Targeted Polymorph Screening Approach for a Complex Polymorphic and Highly Solvating API and Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?
- To discuss further, please contact us via this form or .
References
[5] Brittain H. G., Polymorphism in Pharmaceutical Solids. 2nd Ed. Informa Healthcare; 2009.