| The consequences of Abbott Laboratories' | | | | granulation, melting, spray drying, compression and |
| antiretroviral drug Ritonavir, used to treat HIV | | | | milling that are required to produce the final dosage |
| infection and AIDS and problems with polymorphism | | | | form. |
| has yet to be universally understood. Avoiding | | | | X-Ray Powder diffraction and Raman spectroscopy |
| action has not yet widely been taken on | | | | are the two workhorse methods used to evaluate |
| polymorphism by the global pharmaceutical industry, | | | | the presence and amount of different polymorphic |
| so it is worth repeating the story. | | | | forms found during screening. Differential Scanning |
| In 1996 Abbott launched on the market an effective | | | | Calorimetry (DSC), Differential Thermal Analysis |
| protease inhibitor Norvir® that had cost the | | | | (DTA), Dynamic Vapour Sorption (DVS) and hot |
| company in excess of $200 million to develop. The | | | | stage microscopy are additional specialised techniques |
| drug was formulated as an encapsulated ethanol | | | | used to characterise different polymorphic forms. |
| water solution. In the summer of 1998, supplies of | | | | All is not doom and gloom as the polymorphism |
| the drug were interrupted by the appearance of a | | | | properties of a chemical substance are patentable. |
| new crystal form (polymorphism) at a plant in the | | | | A new polymorphic form therefore may be used to |
| USA and then later at a plant in Italy. This new, | | | | extend the patent life of a drug. A counter to this |
| more thermodynamically stable polymorphic form had | | | | is that a new polymorphic form with advantageous |
| very different physical properties than the earlier | | | | properties may be able to supersede an existing drug |
| material and Abbott was forced to withdraw the | | | | and effectively ‘bust' the original patent. |
| drug from sale. The new form failed dissolution tests | | | | It's not surprising to learn that manufacturers & |
| and precipitated out within the capsules. The | | | | developers of generic drugs actively pursue new |
| company lost an estimated $250 million in sales as | | | | polymorphic forms of patented drug substances. |
| well as hundreds of millions of dollars trying to | | | | This can be a highly litigious area. |
| recover the original polymorph while the product was | | | | National regulatory authorities require that all |
| off the market. No doubt many AIDS sufferers | | | | companies register the precise polymorph of any |
| were not helped by the product's absence. What | | | | new drug. Moreover, manufacturers need to |
| appeared to have happened was that a degradation | | | | demonstrate that each polymorph is stable and can |
| product obtained during manufacturing had initiated | | | | be reliably reproduced |
| the appearance of a second crystalline form, a | | | | Many small pharmaceutical companies do not intend |
| second polymorph. | | | | taking their drug candidates all the way to |
| So what is polymorphism? It is simply a different | | | | commercialisation themselves but to seek to license |
| arrangement a molecule might adopt in a crystal. | | | | at an earlier stage. This arises because of the |
| Most drug molecules are crystalline. That is, the | | | | considerable increase in costs as a drug moves |
| molecules pack together in a particular regular way. | | | | through the clinic. If a polymorph screen is also |
| Some molecules, perhaps most, are able to pack | | | | included then the package is certainly stronger and |
| together in more than one way and thus give rise to | | | | the licensor can expect a further premium. |
| different polymorphs. A pair of polymorphs might | | | | During pre-clinical development the quantity of an API |
| have very different physical properties. Over 50% | | | | that is available for studies is usually very low. |
| of all Active Pharmaceutical Ingredients (APIs) exist in | | | | Screening a wide variety of solvents and conditions |
| at least 2 polymorphic forms. | | | | needs to be conducted for that reason on a very |
| During drug development, an initial scouting | | | | small scale. Systems that can handle multiple |
| polymorphism screen is designed to find a stable | | | | experiments at the milligram scale are best. At |
| non-solvated form with good properties. A later | | | | some labs automated systems can handle up to 96 |
| comprehensive polymorphism screen is to find as | | | | well plate formats and conduct experiments at |
| many forms as possible in order to exhaustively | | | | 0.5-2mg scale. Thus the total amount of API used |
| cover the Intellectual Property space. Continuous | | | | for an initial screen can be a modest 50-200mg. |
| monitoring is needed throughout development in | | | | Typically, a salt selection project will precede a |
| order to ensure continued control of polymorphism. | | | | polymorphism study: once a salt is found that has |
| What can cause polymorphism changes? | | | | the most promising properties, it will be further |
| Crystallisation from different solvents may give rise | | | | developed, characterised and might be the subject of |
| to different crystal forms or solvates. Extremes of | | | | a further polymorphism screen during the normal |
| humidity or heat are among the more obvious | | | | course of pre-clinical development. |
| factors affecting polymorphism. Changes in | | | | Polymorphism, in addition to complicating drug |
| polymorphism can also be induced as a consequence | | | | development also aids drug efficacy and can ensure |
| of several common stages of API processing such as | | | | that any hard earned work is justifiably rewarded. |