I moved back to Spain nearly four years ago, but I still reminiscence of the time I spent in England and Northern Ireland. We didn’t get snow every winter there, but, every now and again, dawn would bring with it an immaculate white blanket, which seemed to cover even the sounds of the street. There was a quiet magic in the air during those days, a momentary pause when the first snowflake landed delicately in the palm of your gloved hand.
We don’t get snow where I live now, but I still remember it covering the fields in Cambridgeshire or Co. Armagh, and I still get mesmerized by its intricacy. Each snowflake —a crystal formed from the simplest molecule, water— is astonishing in its diversity. But this isn’t just a moment of idle wonder. This natural phenomenon prompts reflection on something crucial to my field of work: the many crystalline forms that a substance, even as fundamental as a molecule, can adopt.
Like snowflakes, small molecule pharmaceuticals often display crystalline diversity. We refer to this phenomenon as polymorphism, the ability of a compound to crystallize in more than one crystalline form. Polymorphs can exhibit different physical and chemical properties, and while this might seem like an academic curiosity, their impact touches our lives profoundly. The diversity of solid forms drives innovation in drug development, influences manufacturing decisions, and, sometimes, determines whether a life-saving therapy can reach patients at all.
The remarkable patterns observed in snow crops arise from a single, simple phenomenon: hydrogen bonding. Water molecules joined together in ordered arrangements, influenced by temperature, humidity, and atmospheric pressure. No two snowflakes are alike because these variables are never identical at any moment.
Polymorphs form through analogous processes. Small molecules organize into repeating three-dimensional arrays, with each unique arrangement leading to a distinct polymorph. The exact structure depends on various factors: molecular shape, flexibility, solvent, impurities, and the crystallization process itself. Even slight changes can give rise to different polymorphs, just like environmental changes during a snowflake’s journey result in their uniqueness.
But the importance of polymorphs doesn’t stop there. The different properties of these forms can impact a drug’s shelf life, how quickly it dissolves, and how effectively it interacts with the patient’s body. Understanding and controlling this diversity is critical in pharmaceutical science.
Polymorphism isn’t just a fascinating phenomenon, it’s a practical challenge with high stakes in pharmaceutical development. Consider the infamous case of the HIV protease inhibitor ritonavir, which has been previously discussed in our blog. In the late 1990s, the drug suddenly began crystallizing in an unanticipated and thermodynamically more stable polymorph during manufacturing. The new form had dramatically reduced solubility, rendering it ineffective at therapeutic doses. Production was halted, costing the manufacturer tens of millions of dollars and delaying treatment for countless patients.
This episode stressed the importance of thoroughly understanding the polymorphism of APIs. Crystalline forms can appear unexpectedly, often during scale-up, storage, or changes to the manufacturing process. Scientists must screen and study these forms rigorously to avoid surprises that could disrupt a development program or risk patient outcomes.
Molecular structures themselves often predispose compounds to form polymorphs. Factors contributing to polymorphism include molecular flexibility —flexible molecules with rotatable bonds often adopt multiple packing arrangements—, hydrogen bonding ability —functional groups capable of forming hydrogen bonds, such as -OH or -NH groups, often give rise to diverse crystalline forms by exploring different bonding networks—, and planarity and symmetry —highly planar or symmetrical molecules sometimes stack into multiple layered arrangements, producing polymorphism.
Another aspect involves external factors, such as the choice of solvent in the crystallization process. Polar solvents might promote one form, while non-polar solvents may lead to another. Cooling rate, water activity, temperature, the presence of seed crystals, or stirring intensity all influence outcomes.
Much like the ever-changing conditions that sculpt a snowflake mid-air, these variables create countless potential crystalline arrangements during polymorph formation. Since each new crystalline form will display different properties, all these variables generate a myriad of opportunities to optimize the properties of the small molecule organic compounds, depending on the application for which they were designed.
Whether it is modifying their solubility and dissolution profile, thus improving their therapeutic effect, increasing their stability and shelf-life, reducing manufacturing risks or extending their life-cycle by the generation of novel intellectual property, the investigation of polymorphism in small molecule active pharmaceutical ingredients is an area that should be considered with the same curiosity and wonder which with we contemplate the snowflakes forming in the midst of the winter.
The role of polymorphism extends beyond research labs and manufacturing facilities, it touches patients’ lives in profound ways. When scientists understand and manage crystalline diversity effectively, they bring medicines to market that are safe, effective, and reliable.
Yet polymorphism also serves as a metaphor for adaptability and resilience. Just as snowflakes remind us of the beauty that arises from complexity, polymorphs remind us of matter’s capacity to explore diverse forms under the constraints of physics and chemistry. These explorations fuel discovery and innovation, enabling us to address the challenges posed by disease with increasingly sophisticated tools.
On a final note, just like differences in the binding patterns of the molecules of water can lead to different snowflakes, differences in the growth rates of their crystal faces shape their unique and intricate morphology. The same principle applies to pharmaceutical crystals. The varying speeds at which different crystal faces grow can lead to diversity in the shape and surface texture of the crystals. These differences in morphology and crystal habits, much like snowflakes, are influenced by subtle environmental factors during growth, such as temperature, solvent type, and supersaturation. For APIs, these variations can also profoundly impact processing behaviors. Snowflakes and pharmaceutical crystals may seem worlds apart, but they share a lesson: even the simplest building blocks of matter can manifest in extraordinary ways. Whether sculpted by the cold winds of a winter storm or by the deliberate hand of a chemist, crystalline diversity is a reminder of nature’s capacity for variety, beauty, and practicality. Let this reflection inspire us to continue exploring, questioning, and appreciating the profound complexities of the molecular world.
