Polymorphism: an evaluation of the potential risk to the quality ofdrug products from the Farmácia Popular Rede Própria Olímpia Maria Martins Santos1,2, Maria Esther Dias Reis2, Jennifer Tavares Jacon2, Mônica Esselin de Sousa Lino2, Juliana Savioli Simões2, Antonio Carlos Doriguetto1,2,* Institute of Chemistry, Federal University of Alfenas, Alfenas, MG, Brazil; 2Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, MG, Brazil 1 Polymorphism in solids is a common phenomenon in drugs, which can lead to compromised quality due to changes in their physicochemical properties, particularly solubility, and, therefore, reduce bioavailability. Herein, a bibliographic survey was performed based on key issues and studies related to polymorphism in active pharmaceutical ingredient (APIs) present in medications from the Farmácia Popular Rede Própria. Polymorphism must be controlled to prevent possible ineffective therapy and/or improper dosage. Few mandatory tests for the identification and control of polymorphism in medications are currently available, which can result in serious public health concerns. Uniterms: Polymorphism. Medicines/quality control. Medicines/solubility. Medicines/bioavailability. O polimorfismo em sólidos é um fenômeno frequente em fármacos e pode levar a problemas na qualidade dos medicamentos por alterar suas propriedades físico-químicas, em especial a solubilidade e, consequentemente, a biodisponibilidade. Nesse trabalho realizou-se levantamento bibliográfico sobre os principais estudos e problemas relacionados ao polimorfismo em fármacos presentes nos medicamentos disponibilizados pela Farmácia Popular do Brasil. O polimorfismo deve ser controlado a fim de evitar possível ineficácia terapêutica e/ou dosagem inapropriada dos medicamentos. Destacamos que são poucos os ensaios obrigatórios para identificação e controle desse fenômeno em medicamentos, o que pode acarretar grande problema de saúde pública. Unitermos: Polimorfismo. Medicamentos/controle de qualidade. Medicamentos/solubilidade. Medicamentos/biodisponibilidade. INTRODUCTION The Brazilian Governmental Program Farmácia Popular Rede Própria was implemented to ensure access to low-cost medications that are considered essential for health for Brazilian citizens (Brasil, 2003). Some medications are manufactured and distributed through this nationwide chain. The Farmácia Popular Rede Própria is managed by Fundação Oswaldo Cruz (FIOCRUZ). The list of available medications is defined by the Ministry of Health based on epidemiological studies of the Brazilian population (Brasil, 2004). The drugs analyzed herein are all from the Farmácia Popular Rede Própria, which is Correspondence: A. C. Doriguetto. Instituto de Química, Universidade Federal de Alfenas. Rua Gabriel Monteiro da Silva, 700 – Centro – 37130-000 – Alfenas - MG, Brasil. E-mail:
[email protected] * hereafter referred to as FPRP. Drug formulations provided by the FPRP are typically solid, which is consistent with the findings of a survey published in 2010 that revealed that over 80% of all medications are commercialized as tablets (Thayer, 2010). This predominance of solid drug formulations reflects the greater chemical stability of solid state compared with liquid state formulations (Nunn et al., 2005; Lee et al., 2011). Moreover, the development, manufacture, transportation, storage and supply of solid state formulations are simpler and less expensive in comparison to liquid state formulations (Nunn et al., 2005). However, solid state formulations also present challenges, such as polymorphism (Lee et al., 2011). This review focuses on the current knowledge of polymorphism in solid pharmaceuticals and the potential risk to the quality of drug products provided by the FPRP. Review Brazilian Journal of Pharmaceutical Sciences vol. 50, n. 1, jan./mar., 2014 http://dx.doi.org/10.1590/S1984-82502011000100002 2 O. M. M. Santos, M. E. D. Reis, J. T. Jacon, M. E. S. Lino, J. S. Simões, A. C. Doriguetto POLYMORPHISM Definition and General Considerations Polymorphism occurs when a solid compound exists in two or more crystal forms. Polymorphs are compounds with an identical chemical composition in which the molecules are arranged in at least two different ways in the crystalline state (Bilton et al., 1999; Karpinski, 2006; Desiraju, 2008; Purohit et al., 2009). In pharmaceutical science, however, the term is used to designate several solid state forms of drugs and excipients, including amorphous forms, solvates, hydrates, salts and co-crystals (Aaltonen et al., 2009). The amorphous form does not possess a defined order in its arrangement. Although the amorphous form is the most soluble form, it exhibits the lowest stability (Haisa et al., 1974; Lowes et al., 1987; Chieng et al., 2009). In amorphous and crystalline forms, a solid drug may be anhydrous or a solvate/hydrate. When a solid form contains a solvent, it is known as a solvate. When the solvent is water, it is termed a hydrate (European Pharmapoeia, 2008). Due to the frequent presence of water in the environment and its use in solvent blendings during the crystallization process, the formation of hydrated drugs is common. Because the water molecule is small and able to form hydrogen bonds, it is easily incorporated into the crystalline lattice of drugs both occupying spaces and stabilizing the structure (Gillon et al., 2003). A survey performed in 1999 on drugs described in the European Pharmacopoeia revealed that one-third of the 808 products listed therein could form hydrates (Griesser, 2006). In Brazil, drugs commercialized as hydrates include the following: amoxicillin trihydrate, ampicillin trihydrate, cephalexin monohydrate, sodium dipyrone monohydrate, lidocaine hydrochloride monohydrate, meropenem trihydrate, methyldopa sesquihydrate, pantoprazole sesquihydrate, morphine sulfate pentahydrate, and dexamethasone acetate monohydrate (Farmacopeia Brasileira, 2010). In addition to molecular crystals, drug anhydrates or solvates/hydrates, co-crystals, and salts also occur. Co-crystals are drug solids defined as multicomponent molecular crystals in which at least one of the compounds is an active pharmaceutical ingredient (API) (Bond, 2007; Schultheiss et al., 2009). Salts are considered different from co-crystals provided that they are crystals formed by ionic multicomponents (Mohamed et al., 2009). The FDA has recently published a Regulatory Classification of Pharmaceutical Co-Crystals (FDA, 2013) in which co-crystal is defined as “Crystalline materials composed of two or more molecules within the same crystal lattice” and polymorphs as “Different crystalline forms of the same drug substance. This may include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms”. However, the definitions for these solid forms are matters of debate among the scientific community, regulatory agencies, and industrial groups, without a clear consensus (Schultheiss et al., 2009; Aitipamula et al., 2012). Moreover, a nomenclature for polymorphs has not been established. Generally, different polymorphic forms of identical molecules are denoted by numerical (Carstensen, 2001) or alphabetical sequences; they can also be differentiated by means of hydration or solvation levels. In general, polymorphs are designated by the chronological order in which they have been reported (Carstensen, 2001). The occurrence of polymorphism and its effects on solid products are attributed to existing intermolecular bonds. These noncovalent bonds, such as hydrogen bonds and van der Waals, π-π, and electrostatic interactions, determine the arrangement of the molecules in a crystal (Desiraju, 1995, 2001; Moulton et al., 2001; Purohit et al., 2009). API molecules are produced by atoms connected by covalent bonds, whereas crystals consist of molecules arranged through intermolecular interactions. The differences in these interactions can lead to distinct polymorphic forms and vice-versa (Blagden et al., 2007). Any variation in the intermolecular arrangement of solid materials will alter the physical and chemical properties because these characteristics are intrinsically determined by its crystalline form, with the possibility of affecting bioavailability and stability (Byrn et al., 1999; ICH Q6A, 1999; Bauer et al., 2001; Erk et al., 2004; Lee et al., 2011). According to Lee et al., 2011, the properties that vary as a consequence of the polymorphic form of the active pharmaceutical ingredient are the following: a) chemical: chemical reactivity and photochemical reactivity; b) kinetic: the rate of dissolution and stability; c) mechanical: compactability, hardness, powder flow, and friability; d) physical: conductivity, density, hygroscopicity, and particle morphology; e) surface: interfacial tension, surface area, and surface free energy; and f) thermodynamic: chemical potential, free energy, and solubility; enthalpy and entropy; heat capacity; melting and sublimation; and vapor pressure. Bauer et al. FDA. in which patients were deprived of this important medication (Peterson et al. whereas form B. including polymorphs. 2009). the more stable polymorphic form also complies with requirements described in the Q6A Guide of the International Commission on Harmonization (ICH) for solid form selection (Grant et al. 2001). 2000. choosing the incorrect polymorphic form or the occurrence of a phase transition during the manufacture and storage may affect the bioavailability and. In addition to being easily controllable. 3 consequently. 2008). several lots of capsules did not pass the dissolution test due to the appearance of a new polymorphic form (denoted form II) that had formed during the manufacturing process. A similar situation occurred with rotigotine. The Biopharmaceutical Classification System (BCS) may provide useful information to develop strategies to control polymorphism because the solubility. Originally licensed as a polymorphism-free API.. 2006). medications available in the ‘FPRP’ program (Brasil. Considering solid formulations. the medications must release the appropriate amount of API at a suitable rate for the desired therapeutic effect and be bioequivalent to the reference product..5 (Amidon et al.. particularly for drugs for which dissolution is the absorption-limiting factor (classes II and IV) (FDA. 2011..Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria Challenges for the Pharmaceutical Industry One of the first reports concerning the influence of polymorphism on drugs dates back to 1967 (Aguiar et al.. consequently. Dannappel. which is more stable. 2012). 1967). 2012) were selected for this study to perform a bibliographic survey on the occurrence of polymorphism. Moreover. in 2008. Although the effects of polymorphism on drugs have been known since the 1960s. low solubility and high permeability. low solubility and low permeability. The reformulation of Norvir® using the more stable form required approximately one year. Bioequivalence and Bioavailability To reach an expected therapeutic aim. 2005). 2004). The impact on the standard of living of these patients caused by drug polymorphism highlights the serious consequences of drug polymorphism as a public health concern. KNOWN CRYSTAL FORMS OF APIS PROVIDED BY THE FPRP Table I summarizes the different APIs distributed by the FPRP as solid pharmaceutical formulations. A drug is considered to have high solubility when its highest recommended dose is soluble in 250 mL of aqueous medium in a pH range of 1-7. the efficacy and safety. In 1998.. During the development of Norvir®.. which is metastable. Hilfiker. the medication was removed from the market due to the inability to manufacture the desired polymorphic form (form I) (Lee et al. its possible influence on the physicochemical properties of the API and. 2007.2008). the number . it is imperative that pharmaceuticals exist at the expected concentration. high solubility and high permeability. rotigotine (Neupro ®) was removed from the market due to the transformation into a less soluble polymorphic substance that had crystallized and was not absorbed by the skin (Goldbek et al. only a single polymorphic form was identified. it was only until the case of Norvir® (ritonavir). Thus. 2004. 1995).9%) solid formulations from the FPRP. Despite 79 of 113 (69. Abbott Laboratories was required to spend hundreds of millions of dollars with an estimated loss of US$250m in sales in 1998 alone (Goldbek et al. Schwarz Pharma commercialized rotigotine in 2006 as a transdermal medication to treat the signs and symptoms of Parkinson’s disease (Goldbek et al. the chosen form is typically the most stable (Shingal et al.. did not exhibit adequate bioavailability. According to the BCS. Due to its strategic importance for public health. 2011). and permeability of an API are determinants of its bioavailability.. that highlighted polymorphism as a serious concern for the pharmaceutical industry (Aaltonen et al. When the occurrence of two or more solid forms of an API. for which the therapeutic class and relevant information on polymorphism are also included. III. is identified during the development of a drug. drugs are subdivided into the following four categories: I. Form A.. dissolution.. and IV. Considering that polymorphic forms of an API can exhibit different solubility levels. on the final quality of the pharmaceutical formulations.. high solubility and low permeability.. 2011). II. which is used for the control of acquired immunodeficiency syndrome (AIDS). 1967). these formulations must exhibit physicochemical stability within their shelf life (Aulton.. exhibited greater bioavailability (Aguiar et al. which was more stable and not very soluble (Chemburkar et al. the bioavailability of chloramphenicol palmitate in suspension was evaluated in humans. In this study. and it was concluded that the distinct A and B polymorphic forms exhibited not only different dissolution rates but also differences in serum levels. To resolve this issue. Llinàs et al. Von Raumer. 2011). Nevertheless. 2012. M.. 1978) (Otsuka et al. Bilton et al. 2011. 1983) (TSRL inc. Cody et al. 2004) (TSRL inc. Yoshida et al. Chiou et al. McGregor et al. 2008. 2002. 2012.. Miroshnyk et al. 2002.. 2008.. 2012. 2012. Gala. 2010) (TSRL inc.. Kennedy et al. 2012. 2012) (TSRL inc. Fabbiani et al.. Simões. 1976) . 2009... 1987. Stephenson et al. 2005. Naumov et al. S. Peterson et al. Go et al. J. 1983.. Santos. 2009) (TSRL inc. Doriguetto TABLE I . Kasim et al. 1979. 2012.. J.Solid-state forms of Farmácia Popular drugs API Indication BCS # Stable form* Acyclovir Antiviral III 6 I Acetylsalicylic Acid Analgesic IV 2 I Ibuprofen Analgesic II 2 I Acetaminophen Analgesic IV 6 I Albendazole Anthelmintic II 2 II Mebendazole Anthelmintic II 3 A Loratadine Ferrous sulfate Folic acid Diazepam Amiodarone hydrochloride Antiallergic Antianemic Antianemic Antianxiety II † IV II 2 3 1 2 ‡ ‡ Dihydrate ‡ Antiarrhythmic II 1 ‡ Antiarrhythmic I 3 Amorphous Digoxin Verapamil hydrochloride Amoxicillin Antiarrhythmic. 2012.. Antihypertensive Antibiotic II 1 ‡ IV 1 Trihydrate Azithromycin Antibiotic II or IV 3 Dihydrate Benzylpenicillin Cephalexin (hydrochloride or sodium salt) Antibiotic I or III 1 I Antibiotic II 8 IV (monohydrate) Ciprofloxacin Antibiotic III 3 II (hydrate) Doxycycline Antibiotic IV 2 ‡ Erythromycin Antibiotic IV 4 Dihydrate Sulfamethoxazole Antibiotic IV 4 III (hemihydrate) Sulfasalazine Antibiotic II 2 ‡ Trimethoprim Antibiotic IV 1 ‡ Reference (TSRL inc. Mastropaolo et al. 2012. Montejo-Bernardo et al. Fabbiani et al. Erk et al. Jacon. 1983.. 2012) (TSRL inc. Pranzo et al. 2010) (TSRL inc. Lino. Parkin et al.. 2012.4 O. Stone et al. 1997.. Vishweshwar et al. C.... E. Sohn et al. 2010) (TSRL inc... Rodriguez-Caabeiro et al. Klein et al. Maury et al. Blanco M et al. 2007) (TSRL inc. M. 2012. 2010) (TSRL inc. 1980. 2003. Khunt.... Eberhard et al.. 2011) (TSRL inc. 2003. 1985..... Price et al. Fabbiani et al... 1976) (TSRL inc. Reis... Camerman et al. Fioritto et al. 2009... 2006) (TSRL inc. Dexter et al. Kristl et al. 2004. 1996. Stephenson et al. 2012. Boles et al. 2012. Legendre et al. 2012. Koetzle et al. Hartauer et al..1980) (TSRL inc. 2012. Ferreira et al. 1999) (Wehner et al. 2001) (TSRL inc. 1994. 2008.. Takasuka et al.. Filip et al. M. 2002. Bond et al.. 2012. 1999. 1998.. 2005.. E.. 1998. Shankland et al.1972) (Wu et al. 2005. 2005. T... Lutker et al. 2004. 2012. 2012. Fukumori et al. 1989) (TSRL inc. 2012.. Martins et al. S. Tutughamiarso et al.2001... M. 1985. Derollez et al... Carpy et al. Fabbiani et al. 1992. Haisa et al. 2012.. Aguiar et al. 1974.. A. 1996.... 2012. 2011) (TSRL inc. 2009. 2011) (TSRL inc. Turel et al.. D.. 1978) (TSRL inc.. 2012. 2004) (TSRL inc. Peeters et al.. 1996) Antiepileptic † 1 Ketoconazole Antifungal II 2 I I (enantiomer +) Fluconazole Antifungal III 4 I Miconazole Nitrate Promethazine hydrochloride Antifungal † 3 ‡ (Chananont et al. Uekama et al.. 2012) Atenolol Antihypertensive III 2 I Captopril Antihypertensive III 2 I (B) Enalapril maleate Antihypertensive I 2 II Losartan Antihypertensive III 5 I Methyldopa Antihypertensive III 1 ‡ Nifedipine Antihypertensive II 3 A= I= α Propranolol hydrochloride Antihypertensive I 3 II Simvastatin Antilipemic II 3 I Biperiden Carbidopa Antiparkinsonian Antiparkinsonian I I 1 ‡ I ‡ Amitriptyline hydrochloride Fluoxetine hydrochloride Glibenclamide Metformin hydrochloride Metoclopramide hydrochloride Clonazepam Reference (TSRL inc. 2012. 1997. Bredikhin et al. 1984) (TSRL inc. 1989. Lisgarten et al. Husak et al... Byrn et al. Wu et al. 1979. Gelbrich et al.. Jindai. 1979) (Peeters et al. 1988) Antidiabetic II 1 I (TSRL inc. 1981. Wu et al. 2004. 2003.. 2012.. Harris et al. 1994) Antidepressant I 1 I (TSRL inc.. 2012. Codding. 2004.. Kiang et al. Zencirci et al... Lang et al.. Peeters et al. 1987. Kulkarni. 1981.. 2011) (Pedersen et al. Evjolfsson.. 2004) (TSRL inc. 2002. 2012.. 1986) (Lindenberg et al. 2012. 1993. Fernández et al.. Cejka et al. Gunn et al... 1997. 2012. Zencirci et al.. Alkhamis et al. 2012.) API Indication BCS # Stable form* Carbamazepine Anticonvulsant II 6 Dihydrate Phenytoin Anticonvulsant II 1 I Phenobarbital Anticonvulsant IV 13 A Antidepressant I 1 I (TSRL inc.. Childs et al. 1986.. 1993.....Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria 5 TABLE I . Rebou et al. 2005. 2012. 2012.. 2009. 2011) (TSRL inc.. 2004) Antihistamine I 2 ‡ (TSRL inc. Haoming et al. 2002.. 2005. 1997.. 2012. 1999. Kogan et al.. 1992. 1986) Antidiabetic III 2 A (TSRL inc. Fekete. Esteves De Castro et al.. Klein et al. 2012. 2010) (TSRL inc.. Robertson et al. 2003. 2003. 2002... 2012. 2012. 2012. 2005) (TSRL inc. Zhenhong et al. 2004) Antiemetic II or IV 3 ‡ (TSRL inc. Platteau et al. 2004) . Nokhodchi et al. Grooff et al. Grzesiak et al.. Borodi et al. Neuman et al. Himes et al. 2011) (TSRL inc.. 2012.. Otsuka et al.. Caira et al.. 2008. Dolitzky et al.. 2004. 2007) (TSRL inc. 2012. Tessler et al. 2012.. Arlin et al.. 1993. Pabón et al. 2003) (TSRL inc.. Bartolomei et al. Chandavarkar. 2010) (TSRL inc... 2006. Précigoux et al.. 2012. Lowes et al. 2003) (TSRL inc. 1985..Solid-state forms of Farmácia Popular drugs (cont.. Campbell et al. 2012) (TSRL inc. 2012.. Kieczykowski et al. known crystal structures and correct polymorph reported in the literature that is present in the medication for each API. 2005) (TSRL inc. 1970.. 1989) (TSRL inc.. The Cambridge Structural Database (CSD... Mostad et al. hydrates. McDowel. Hempel et al. Rao et al. M. *: Room temperature. 2011) and Inorganic Crystal Structure Database (ICSD. M. Kang et al. 2012. 2008) (TSRL inc. Lulla et al.. Reisch et al. 2012. 2012.. 1975. 2008) (TSRL inc. 2012. 2002) was used to analyze crystalline structures by entering the compound name. 2009) (Lindenberg et al. E. Cook.. Galván-Tejada et al. salts.Solid-state forms of Farmácia Popular drugs (cont. Reis. 1994...1984) (TSRL inc. J. 1993) mononitrate #: minimum number of known crystal structures. Agatonovic-Kustrin et al. 2012. 1996.. Shikii et al.. Guguta et al. S. Howard et al. Santos. 2010. 2002) (TSRL inc. 2006) Oseltamivir phosphate Antiviral I or III 1 ‡ (TSRL inc.. Acharya. M.. and solvates with pharmaceutical application.. Prusiner et al. of different solid APIs is 65. molecular form. Leech et al.) API Indication BCS # Stable form* Antiparkinsonian I 2 I Antiparkinsonian † ‡ ‡ ‡ Antiprotozoal IV 1 ‡ Chlorpromazine Antipsychotic II 2 Anhydrous Haloperidol Omeprazole Antipsychotic Antiulcer II † 1 1 I ‡ Ranitidine hydrochloride Antiulcer III 4 II (TSRL inc. 1993.. 2012. 2001) (Ohishi et al. Simões.. Vertzoni.. †: Unclassified. neither salts and solvates without pharmaceutical application nor co-crystals were considered. Furthermore. 1986) (TSRL inc.. 2012.. and ‡: Not reported. Mostad et al. Note: For the overall polymorphic forms. Vega et al. 2012. Ngooi et al. 2004. 2004... which is managed by Amidon et al. 2012. Klein et al. 2010) (TSRL inc. Chieng et al. Doriguetto TABLE I . 2012... 2012) Bronchodilator I 3 I (Lindenberg et al. 2007) IV 1 I (TSRL inc. Chen.1990. 1972) I I 1 2 Hemihydrate ‡ Levodopa Benserazide hydrochloride Metronidazole Salbutamol sulfate Ethinyl estradiol Levonorgestrel Chronic gout treatment Contraceptive Contraceptive Norethisterone Contraceptive I 1 ‡ Furosemide Hydrochlorothiazide Prednisone Diuretic Diuretic Glucocorticoid IV IV I 3 2 1 I ‡ ‡ Immunosuppressant IV 2 ‡ Inhibitor of bone resorption III 13 ‡ Allopurinol Azathioprine Alendronate sodium Reference (TSRL inc. Asnani et al. 1969. 2012 (TSRL inc 2012). E. Babu et al. Bugg. M. This difference is due to the availability of more than one dosage for an identical API. 2007. Finkelstein et al. 1999. C.. 2004... D. Jacon. 1995) (TSRL inc. 2009) Isosorbide Vasodilator I 2 ‡ (Fotaki. 2000. Kanters et al. Compound structures were included as single component forms. 2011. J. and chemical structure. 1971. T. S. Suitchmezian et al. 2008) (Vogt et al. Biopharmaceutical classification was obtained at the Therapeutic System Research Laboratories.. Palacio et al. Table I also includes the BCS class. 2011... a search was performed using the aforementioned electronic databases by combining the terms “name of the compound in English” and . Chang. A.6 O. 2012. Lino.. 2012. Information on patents and indexed journals in the electronic databases SciFinder© (2012) and Web of Science © (2012) were also collected. Prasanna et al. . Albendazole is commercialized in form I (metastable). as previously mentioned. For 21 (68%) of the 31 class II and IV APIs (low solubility). two or more polymorphic structures have been reported. 37%) without studies indicating the correct crystal form. 2010). of which 13 (54%) have two or more known polymorphic crystal structures.Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria “polymorph” in the free search of databases. and acetaminophen.. Only 21 (32%) APIs do not exhibit more than one reported crystal form. II = high permeability. Figures 1c and 1d show the BCS classification of the 65 solid APIs available at the FPRP. (c) the distribution in the BCS (I = high permeability. The revision work also indicates that no crystal structure is known for 2 (3%) APIs listed in Table 1. two or more crystal structures have been reported. However. Table I indicates that phenobarbital and alendronate sodium are the APIs with the most reported polymorphic crystal structures (11 forms each) followed by cephalexin (8 forms) and acetaminophen/carbamazepine/acyclovir (6 forms each). and (d) the distribution in the BCS indicating the APIs with high solubility (classes I and III) and low solubility (classes II and IV). much care is required to control the form because of the possibility of undesirable polymorphic phase conversion in this API (Pranzo et al. it is important to emphasize that in this review. “only one”.3%). carbamazepine.. (b) the types of solid forms expected to be present in the solid formulation. only polymorphs deposited in the CSD© and ICSD© or in articles indexed in SciFinder© and Web of Science© were considered.67 polymorphs per API. i. Noteworthy is the number of APIs (24.. Figure 1a illustrates that 42 (65%) of the 65 APIs exhibit two or more polymorphs of known crystal structure. estradiol. which differ in their biopharmaceutical and physicochemical properties. for mebendazole. Both forms I and II are stable under storage conditions. A total of 168 crystal structures were found for the 65 APIs listed in Table I. B. Articles that discussed solid state chemical polymorphism were included. Form A is the most FIGURE 1. Albendazole and Mebendazole The antiparasitic albendazole and mebendazole are among the low solubility drugs with reported polymorphism. which is the most soluble form. Statistical features of the 65 APIs available as solid formulations at the FPRP. Mebendazole exhibits polymorphic forms A. Despite 41 (63%) APIs (Table 1) with more than one reported crystal structure. Charoenlarp et al. For some APIs. . Figure 2 7 shows the number of APIs with “unknown”. which resulted in a mean value of 2. low solubility). and IV = low permeability. and “two or more” crystal structures per BCS class. 1993). 1987. high solubility. This result is also summarized in Table I and is illustrated in Figure 1b. high solubility. (a) The number of different crystal structures (polymorphs when there are more than one structure). articles that discussed other types of polymorphism were excluded. there are studies concerning the influence of polymorphism on drug performance for only 22 (14. illustrating that 31 (48%) possess low solubility (classes II and IV). For 17 (68%) of the 25 class I and III APIs (high solubility). low solubility. however.e. III = low permeability. the thermodynamically stable form (or preconized polymorphic form) is reported in the literature. Polymorph C is the pharmaceutically preferred form due to its adequate aqueous solubility (Rodriguez et al. and C. Problems related to either the efficacy or the manufacture caused by polymorphism have been reported. 8 O. Therefore. J. 2003. polymorph B should be avoided or a strategy to ensure the proper dosage must be developed to enable the drug to exert the desired effect. In 2005.. it can evaluate the quality of a medication (Yu et al. recommended for oral use. Therefore. much attention should be directed at quality control methods that are able to discriminate between polymorphic forms and that the polymorphic form present in the medication is the recommended form. Four analyzed trademark drugs presented traces of form A. which resulted in a recommended medium at pH 2. 2008). Villiers et al.. an analysis of the raw materials and drug products containing mebendazole in the Brazilian market revealed the following alarming results: the expected form C was not found in any analyzed raw material. in solution.. five contained polymorph A.. Lino... In this respect. it was observed that the mebendazole dissolution assay described in USP 25 did not distinguish among the three polymorphic forms. 2005). Costa et al.. Jacon. S. 2009). three contained polymorph C.. 1987. as observed with mebendazole. 1987). the USP 34 (2011) continues to recommend a dissolution medium that contains SLS. less soluble form that is considered therapeutically ineffective (Rodriguez et al. stable. Therefore. the mebendazole reference brand (manufactured by Abbott Laboratories) was altered. Doriguetto FIGURE 2. Reis.1992). The number of different crystal structures distributed in the four classes of the BCS for the 65 APIs that are available as a solid formulation at the FPRP. (1991) have shown that polymorph B is more soluble than polymorph C. the recommended dissolution test for furosemide does not discriminate among forms (United States Pharmacopeia. thermogravimetric analyses.. When the solubilities of furosemide polymorphs are compared. Form C. Moreover. characterization using powder X-ray diffraction is very useful. M.. 2009). Therefore. E. Raw et al. several dissolution mediums were tested. the in vitro dissolution assay is an excellent tool to differentiate polymorphic forms and identify polymorphic phase transitions. Polymorph C was not detected in this new reference medication. E. . The recommended dissolution medium was 0. Nevertheless. At the time the study was published. M. The solubility difference among the polymorphs had been masked with the inclusion of the surfactant. 1993). Agatonovic-Kustrin et al. Provided the test anticipates bioavailability and physical stability. S. 1998). Simões. To differentiate furosemide polymorphic forms in pharmaceutical formulations.. Quality control routine tests that may distinguish among polymorphic forms include the dissolution assay. 2010). the efficacy of polymorph A did not differ from the placebo (Charoenlarp et al. and two contained a mixture of polymorphs B and C. M. is metastable and.2 due to its ability to differentiate the commercialized form (form I) from the other forms (II and III) (Maggio et al.. M. in most of them.. From the 10 analyzed medications. regarding stability. may crystallize as the more stable form A (Rodriguez et al. 2004). A. Furosemide Another low solubility drug that exhibits problems related to the dissolution assay in official compendia is the diuretic furosemide. and. Despite this example. the presence of small quantities of form A in tablets results in a rapid increase of transformation into other polymorphic forms. which also contained different polymorphs in different lots (Froehlich et al. 2011). C. thus. 1990). USP reference standard included.1 M hydrochloride acid containing sodium lauryl sulfate (SLS). the anthelmintic efficacy of mebendazole is highly dependent on the polymorphism (Martins et al. Thus. and the removal of SLS from the dissolution medium resolved the polymorphic forms (Swanepoel et al. In a clinical study with 958 children. the shelf life was reduced to less than a month. and primarily powder X-ray diffraction measurements (Liebenberg et al. with B as the majority.. This API has been observed to undergo photolytic degradation from which the metastable forms suffer more than the thermodynamically stable form I (Matsuda et al. IR spectroscopy. J. Santos. These products also failed to comply with the acceptance criteria of the United States Pharmacopoeia (USP) and the Food and Drug Administration (FDA) in dissolution assays (Brits et al. methods that are described in official compendia must be carefully considered because. Considering the diuretic furosemide as an example. 1990. the metastable form II is found to be the most soluble (Matsuda et al. 2003). T. D. which is a great concern considering that this antiarrhythmic has a narrow therapeutic window. The solubility order among the polymorphs of this API is II (metastable) > I > monohydrate (Park et al. A similar phenomenon occurs with erythromycin. 2000.. Carbamazepine The impact of polymorphism has been extensively studied on the anticonvulsant carbamazepine. Lutker et al. As expected. British Pharmacopeia. In 1988. When pure form III samples are compared.. Quist et al. and forms I and II convert into the monohydrate when dissolved in water (Park et al... ciprofloxacin. Lang et al. which emphasizes the need to develop methods to quantify the contamination of form III with other polymorphic forms (Kipouros et al. with a solubility ratio of 1. these polymorphs exhibit different dissolution rates. 2005).... Micronization with supercritical antisolvent has led to an increase in the sulfamethoxazole dissolution rate and has caused the phase transition of polymorph I to II.. 2008). 2003.. 2010). A mixture of polymorphic forms has been observed in commercial samples of carbamazepine raw material (Šehić et al. Erythromycin. Grzesiak et al. For sulfamethoxazole. and Digoxin A tendency to form hydrates is also observed in the antibiotics cephalexin. 1996.. 2012). 2007). Al-Zein et al. 2010. Cephalexin is also found in the dihydrated form. 1999.. . Javadzadeh et al. a phase transition was not observed for form II. a clinical failure was reported for Tegretol® tablets (carbamazepine).. 2009. whereas form I converted to the hemihydrate under identical conditions (Fioritto et al. Acyclovir The acyclovir in pharmaceutical formulations is present as a hydrate (polymorph V) (Kristl et al. 2009. This API loses its water molecules at relatively low temperature (71 °C) (Fukumor et al. United States Pharmacopeia. 2008). 2008.2 (Pudipeddi et al. 1996).. Fluconazole exists as a mixture of forms I and II and fluconazole monohydrate (Park et al... Thermal stress of digoxin also results in polymorphic phase transitions (Eberhard et al. which is explained by the high thermodynamic stability and low hygroscopicity of the anhydrous form (Kristl et al. which is commercialized in its more stable and less soluble dihydrated form. 1979). 2008.. Moreover. 2011). 1999. 2011). Wang et al. 1992. 2012). Diao et al.. there are several reports of variability in the dissolution profile of commercially available carbamazepine tablets (Davidson. Meyer et al.. In pharmaceutical preparations. Chang et al. 1983). Form III converts to carbamazepine dihydrate (a less soluble form) more rapidly than form I.. Fluconazole Fluconazole confirms the high frequency of hydrate occurrence in APIs.... Although such compendia determine form III for medical preparations.. Cephalexin. Storage of the amorphous form at room temperature results in a reduction in solubility (Chiou et al.. Jindai. 1998. which is observed when an aqueous suspension of form I is prepared (Mafra et al.. Kulkarni. Studies revealed that for digoxin. 1994. Unexpectedly. at room temperature. 1997). Mittapalli et al. 2012. 2011). Lake et al.. and sulfamethoxazole. 2010). the effect of particle size on the dissolution rate is counterintuitive. Carbamazepine is one of the few APIs for which the recommended polymorphic form is described in official compendia. Stephenson et al. monohydrated cephalexin is the predominant polymorphic form (Aguiar et al.. 2011). 2002. rapidly loses one molecule of water to form the monohydrated cephalexin (Kennedy et al... 1996. the hydrated form of acyclovir solubilizes more rapidly than the anhydrous form (Kristl et al. 2000). Ciprofloxacin. 2012). likely due to the polymorphic phase transition from the anhydrous to the dihydrate form (Lee et al. As for ciprofloxacin. Polymorph II has been found to absorb humidity and form the monohydrate phase from both the environment and the excipient during either the storage phase or the manufacturing phase (Chandavarkar. 2007). form II converts to the hemihydrate (form III) more rapidly than form I. 1976). 1983)... and the manufacture of this API does not always result in pure crystalline phases (Rustichelli et al. 2011). Flicker et al. 2005.. the grinding process leads to amorphization (Florence et al. particularly for low solubility drugs (Bonfilio et al. which. the exposure of form I (anhydrous) to a relative humidity higher than 90% leads to the appearance of form II (hydrate).. they do not define limits for the other forms (European Pharmacopeia. erythromycin.. Sulfamethoxazole. which critically affects the solubility and bioavailability of pharmaceutical preparations (Kobayashi et al. highlighting its impact on product quality.. 2003). In the 9 solubility assay.Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria the development of methods that are able to differentiate polymorphic forms is essential for the quality control of medications. 2011). T... 1998). Under isothermal conditions (45 °C). It was only in 2005 that polymorphism was verified in this API. M. The increased ratio of sodium hydrogen carbonate in the tablet containing form II and the presence of desiccant in the blister packaging significantly decreased its degradation (Eyjolfsson. and Estradiol Ranitidine.. 1996). S.. E. Reis.. 2012). are stable at room temperature even after grinding and compression. Foster et al. To manufacture medications containing form I. S. Nichols et al. 1998. The order of the dissolution rate among the forms is F > B > E > C > A > D. 2003). with the transformation rate of form D as the fastest (Otsuka et al. In the studies on enalapril. 1997).10 O.e.. and E forms underwent transformation during storage. Transdermal adhesives. Lino. Verapamil Hydrochloride. and F forms were stable at 0 and 75% relative humidity. which occurs because the narrow shape of these particles enables the conversion to the dehydrate (Flicker et al. C.. which is prescribed for the treatment of ulcers. which contain this drug. 2004). mechanical strength (Carstensen et al. in contrast to form I (stable). whereas C. 1999). . which is advantageous because the process is simpler and less expensive (Di et al. Ranitidine. form II was observed to be much less stable than form I in tablets containing an identical amount of sodium hydrogen carbonate (Eyjolfsson. J. A polymorphism effect was also found for estradiol. Enalapril. and form II may convert to form I during storage (Wu et al. Parkin et al. Nichols et al.. and Propranolol For antihypertensive drugs that contain verapamil hydrochloride. Notwithstanding. Every form (I.. J. 2011).. II.. D. and the order of the hardness among the tablets containing them is D > A > C > E > B = F (Otsuka et al. Form II (metastable).0 °C. 1994).. and it was found that this API did not exhibit polymorphic forms at the evaluated conditions (Yoshida et al. 2005). Because the dissolution rate is similar for both form II and commercialized form I tablets. form II was isolated. Acetaminophen Acetaminophen. Crocker et al.4 °C and that of form II of 151. with form III as the most soluble (Sohn et al. 1993). M. and phase transitions can occur via water absorption. 1996... 1994). 2002). Santos. Acetylsalicylic Acid The possibility of the occurrence of polymorphism in acetylsalicylic acid (ASA) antiinflammatory and analgesic products has been investigated since the 1960s (Tawashi.... 1998).. The crystals belonged to different estradiol polymorphs and also to the polymeric adhesive (Variankaval et al. 2006) and during storage (Madan et al. D. Glibenclamide. a slight difference in stability was observed between these forms. which is another analgesic and antithermic drug. 2011). Jacon.. Polymorph I (metastable) is 34% more soluble than form II (commercially available) (Bartolomei et al. were evaluated. a possible transformation does not lead to problems with bioavailability (Di et al. 1995.. E. III. Chieng et al. 1998.. is an example of manufacturing problems associated with polymorphism (Snider et al. which increases the cost (Di et al. 1999). B. phenobarbital stability was as follows: A. and its conversion into form I occurs at room temperature. studies were performed at temperatures varying from 25 °C to 750 °C using several analytical techniques.. 1997. can be used in the manufacture of tablets. and IV) was found to be stable below zero or 100% relative humidity.. D (dioxane solvate). Glibenclamide form I is the most stable with a melting point of 175. 1968). although this process may lead to a phase transition (Bolten et al. formed crystals during storage. Doriguetto i. M. a larger amount of small-sized particles results in a slower carbamazepine dissolution rate. which is accelerated by mechanical grinding (Varughese et al. Micronization of carbamazepine by expansion in supercritical solution appears to increase the solubility of the drug. 1997). C (monohydrate). 1993. Losartan antihypertensive form I is thermo dynamically more stable and less soluble than form II at room temperature. Subsequently. phenobarbital (A.. 2010). Simões. Phenobarbital Six of the polymorphic forms of another anticonvulsant. E (hemihydrate) and F). commercially available agglutinant excipients are required.. 2002). M. Losartan. Both forms I and II of another antihypertensive. B. in which it was found that form II (metastable) coexists with form I (Vishweshwar et al. A. exhibits polymorphic forms I and II with similar solubility and bioavailability (Bawazir et al. propranolol. Conversely. CONCLUSION For many drugs present in medications that are available at the FPRP. S. Powder X-ray diffraction is feasible for application in the quality control of polymorphism in capsules. v.Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria QUALITY CONTROL OF POLYMORPHIC SOLID FORMS Single crystal and powder X-ray diffraction techniques are the most suitable and more utilized tools to study and characterize polymorphs in pharmaceutical solids because they provide unequivocal proof of either polymorphism existence or polymorphism occurrence (FDA.. thermal analysis (e. However.23-37. excipients and drug products (United States Pharmacopeia. Analysing the crystal purity of mebendazole raw material and its stability in a suspension formulation. CAPES (PNPD-2007 and PNPD2011) and CNPq (472623/2011-7 and 476870/2011-9) for their financial support of this study. among others. MANGAN. ACKNOWLEDGEMENTS We thank FAPEMIG (APQ-02685-09. v. 2007) because the test is demonstrably able to differentiate different forms. 2007). p. N. consequently. Therefore.. p. differential scanning calorimetry. T. CAPES. . FINEP (Refs. assays on powder X-ray diffraction are described in only 15 monographs from the 4. M. the existence of polymorphs may potentially be an important source of variation in pharmaceutical properties. I.. S. V. Biopharm.. there are few studies that correlate polymorphism to possible influences on drug solubility as well as its clinical impact. 2008. Sci. The pharmaceutical formulation can be analyzed after minimal or no pretreatment of the sample without a requirement to separate the API from the excipients because most excipients are not detected by X-rays. Pharm. efficacy and bioavailability of drug products.93. Despite the vast accumulated scientific knowledge on the effects of phase transitions in APIs in the solid state. APQ-0109310. n. Crystal structure of 6-((1-methyl-4nitroimidazol-5-yl)thio) purine. 1999. V. 1997). n. Pharm. SAVILLE.. and thermal techniques are considered complementary in the study of polymorphs. For this purpose.. APQ-02600-12.D. MEDR. n. it is possible to simultaneously identify more than one API in the formulation (Phadnis et al. AGATONOVIC-KUSTRIN. Pharm. B. Thus. KORADIA. We thank the CSIC of Spain for the license to use the CSD. RADES.. the identification of the polymorphic phase is not a mandatory test for the large majority of drugs.183-187.g. Eur. the API must be crystalline and be present at a concentration greater than 5% (w/w) in the formulation. 2009..107-114.G. infrared [IR]. in USP 35-NT 30.R. Manufacturing.. n.. and Controls Information that provides recommendations for the monitor and control of polymorphs in drug substances and/or drug products (FDA.2.. Raman. ACHARYA. 2012). which is the commonly adopted detection limit for phase quantification using PXRD techniques. J. p. Powder diffractometric assay of two polymorphic forms of ranitidine hydrochloride. and spectroscopy (e. more commitment is necessary by regulatory and quality control authorities to monitor polymorphism not only for FPRP medications but also for all commercial drugs.71.500 monographs that include APIs. 2007). and PPM-00524-12).. This monitoring includes the control of polymorphism in raw materials.. 1984.245-50. However. WU. Relatively simple quality control tests allow the differentiation of polymorphs..C. the FDA published the Guidance for Industry of FDA ..g. J. S. and pastes. ALLESØ. Indian AS-Chem.184. In this manner. according to the best of the 11 authors’ knowledge. and hot-stage microscopy). RANTANEN. MIRZA.. tablets. possible public health concerns linked to polymorphism in medicines can be avoided. and solidstate nuclear magnetic resonance [ssNMR]) are also commonly used in the quality control of polymorphism in drugs. J. GORDON. which can cause problems concerning the stability.ANDAs: Pharmaceutical Solid Polymorphism Chemistry. p.361. Solid form screening – a review.. v. solubility and. Diffraction. MESL and JSS). J. P. J. GLASS. K. Moreover.1-2. v. and FAPEMIG for research fellowships (ACD. Int. Int. crystalline form characterization assays are not included in most monographs described in official compendia.. REFERENCES AALTONEN.1.1. D. J. AGATONOVIC-KUSTRIN. We also thank CNPq. spectroscopic. 134/08 and 0336/09). Polymorphic transitions can also be detected using drug product dissolution testing (FDA. K. TUCKER.. Others important techniques such as microscopy. thermal gravimetric analysis. 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