Because the atoms in a crystalline solid are held together more tightly (the bonds between molecules and atoms are stronger in crystalline solids), the crystal form of a solid can affect its physical properties like solubility and melting point. Typically, an amorphous solid is more soluble and has a lower melting point. This is important for formulating molecules into drug products.
Polymorphism - Get in Shape!
What is a Crystal?
A crystal is a solid material that at an atomic level is highly structured – its atoms are arranged in distinct and repeating patterns. Not all solids are crystalline, and some can exist in multiple forms.
Crystalline vs Amorphous
Crystalline
A crystalline solid has a regular arrangement of atoms...
Amorphous
...while amorphous solids do not.
Common Crystals
Table salt is a good example of a crystalline solid. Table salt is made of an equal number of sodium (Na) and chlorine (Cl) atoms which are aligned in a very regular pattern as seen at left.
Types of Crystals From One Element
The same materials can exist in different crystal forms and as an amorphous solid. Carbon is an example.
Diamond: a very compact, dense crystal form
Charcoal: amorphous – no crystal structure
Graphite: sheets of rings of carbon atoms make up this crystal form (this is how your pencil "lead" leaves traces of carbon as you drag it across paper)
Detection
How can we know what crystal form we have produced? There are several instruments that can be used to determine crystal form.
Microscopy – the shape and size of crystals can be visually observed under a microscope. Using a polarized light microscope allows confirmation that crystalline solid has been produced as the light refracts differently for a crystal than an amorphous solid.
Powder X-ray Diffraction – the scattering of x-rays through and off a powdered solid sample allows a distinct pattern of peaks that can be used to identify different crystal forms in a bulk powder.
Single crystal X-ray Diffraction – if a large enough single crystal can be grown, x-ray diffraction can be used to identify the actual lattice positions of atoms in the crystalline solid.
How does crystal form affect drugs?
The active ingredients in most of our small molecule products are solids. It is important that when we isolate the final solid, we consistently produce the same crystal form. This assures that each batch of the active ingredient will be of equivalent purity and perform the same way each time we formulate it into the dosage form (tablet, capsule, solution). This includes the performance in the actual production of the dosage form and how that dosage form performs in the body. How does this work?
Purity
Solids form from a concentrated solution. This is how we isolate most of our solid active ingredients. We dissolve the solid mass and slowly reduce the temperature or the composition of the solution. The active ingredient molecules then form crystals that fall out of solution. The goal is for the solids to grow the same way each time, thus making the same form of the crystal for every batch. As the crystals grow, impurities are excluded as they do not fit into the crystal structure. Always growing the same crystal form provides consistency for purity of the final isolated solid.
Solution of API molecules and impurities in solvent
Crystals of API forming, excluding impurities, falling out of solution
Bioavailability
Different crystal forms of the same substance can have differently solubility in the same solvent (or mixture of solvents). To dissolve a solid, bonds holding the crystal lattice in place must be broken. If there is less order to the crystal, it is easier to dissolve that solid. (less energy input is required to break the bonds between the molecules and atoms). This is important when formulating a drug because an active ingredient must dissolve in the body in order to be absorbed.
Hot Melt Extrusion
Hot Melt Extrusion is used to produce solid oral drug products (tablets, capsules) containing amorphous active ingredients. The API is melted along with excipients and when the resulting liquid mixture cools, the API does not reform crystals as it is distributed across the resulting solid mixture. When used in oral dosages, this facilitates dissolution and absorption of poorly soluble APIs by the body.
Free-flowing melted mixture of excipients and API molecules
Solid mixture of excipients and API molecules
