Table 2.

Summarization of polymorphism of several drugs.

Drug Substance	Polymorphism Aspects	Bioavailability Issues
Chloramphenicol palmitate	Chloramphenicol palmitate is a prodrug of chloramphenicol with antibiotic properties [64]. Chloramphenicol palmitate exist in three polymorphic forms: (A, B, C) [65,66], the stable form A (biologically inactive modification), the metastable form B (active modification) and unstable form C [67,68,69]. The three crystalline forms were also called α, β and γ. The α form is unstable at room temperature and gradually transforms to β on storage [70,71].	Form B (β) dissolves faster than Form A (α), and has a much higher solubility [72,73,74]. Low serum levels for the stable polymorph A were observed [75].
Oxytetracycline	Oxytetracycline is a broad spectrum antibiotic. It exists in two different polymorphs [76].	Oxytetracycline showed differences in patients’ blood levels [77] or differences in in vitro dissolution of tablets [78] because of differences in polymorphic forms.
Carbamazepine	Carbamazepine is used in the treatment of epilepsy and trigeminal neuralgia. Different polymorphic forms were described [79,80,81,82,83,84,85,86,87,88,89,90,91]. Four anhydrous polymorphs were characterized: I, II, III, and IV, respectively identified as triclinic, trigonal, monoclinic, and monoclinic [77].	In spite different studies demonstrated similar pharmacokinetics in humans of anhydrous and dihydrate forms of carbamazepine [92] and no differences in bioavailability between a generic carbamazepine product and an innovator product [93], several clinical failures were reported concerning carbamazepine [94,95], in particular with generic carbamazepine tablets [96]. More recently, it was confirmed that the initial dissolution rate of carbamazepine was in the order of form III > form I > dihydrate, while the order of AUC values was form I > form III > dihydrate. This discrepancy may be attributed to the rapid transformation from form III to dihydrate in GI fluids [97].
Ritonavir	Ritonavir is an antiretroviral drug belonging to protease inhibitor class and used to treat HIV-1 infection. Ritonavir exhibits conformational polymorphism [98] and a total of five forms were described [60]. The forms I and II were more extensively characterized [98].	2 years after the launch of the first ritonavir product, several batches failed dissolution specifications because the presence of a different polymorphic form having ~50% lower intrinsic solubility of reference form [36].
Atorvastatin calcium	Atorvastatin calcium is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, with strong ability to lowering blood cholesterol. At least 60 polymorphic forms/solvates/hydrates have been patented [99,100,101]. It is not unusual to verify the presence of polymorphic impurities in the marketed atorvastatin calcium (API) with consequences on drug bioavailability and stability [102].	Atorvastatin is unstable and the hydroxy acid form is converted to lactone form that is 15 times less soluble than the hydroxyl acid form [103,104]. This instability of atorvastatin calcium leading to poor solubility (0.1 mg/mL) is the main cause for low bioavailability of the drug after oral administration as the absolute bioavailability of atorvastatin calcium is only 14% [105].
Axitinib	Axitinib is a tyrosine kinase inhibitor of endothelial growth factor interrupting tumor angiogenesis and thus, preventing the growth of cancer cells. 60 solvates, polymorphs of solvates, and five anhydrous forms were discovered [106,107,108,109].	The commercial formulation under trade name Inlyta® contains the stable anhydrous form [107].
Phanylbutazone	Phenylbutazone is a potent anti-rheumatic drug existing in different polymorphic and solvated forms [110,111,112,113]. Anhydrous forms I and II were more extensively described and form II resulted more soluble than form I. The Form III is a highly unstable form [110].	Anhydrous forms I and II polymorphic forms exhibited different solubilities, dissolution rates and oral absorption [110,114].
Rifaximin	Rifaximin is a synthetic derivative of rifamycin, with very low gastrointestinal absorption, but still displaying a broad spectrum of antibacterial activity [115,116,117]. Rifaximin shows crystal polymorphism (poolymorphs α, β, γ, δ, ε) [118,119]. The polymorph α is the most thermodynamically stable form and the commercial one.	In vitro studies show different dissolution and solubility rates for these polymorphs, and in vivo investigations in dogs found different pharmacokinetic patterns, with δ and γ polymorphs displaying the highest systemic bioavailability [119]. The most PK parameters were significantly higher after administration of generic rifaximin, because of the presence of both rifaximin-α and amorphous forms [120].