«Inauguraldissertation zur Erlangung der W¨ rde eines Doktors der Philosophie u vorgelegt der Philosophisch-Naturwissenschaftlichen Fakult¨ t a der ...»
Impact of Variability in Carbamazepine
Raw Materials on Drug Release
Erlangung der W¨ rde eines Doktors der Philosophie
Philosophisch-Naturwissenschaftlichen Fakult¨ t
der Universit¨ t Basel
Untersch¨ chen, Uri
Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakult¨ t
auf Antrag von
Prof. Dr. Matthias Hamburger,
PD Dr. Gabriele Betz
Prof. Dr. Anna Seelig
Basel, den 21. Juni 2011 Prof. Dr. Martin Spiess Dekan Originaldokument gespeichert auf dem Dokumentenserver der Universit¨ t Basel a edoc.unibas.ch Dieses Werk ist unter dem Vertrag ”Creative Commons Namensnennung–Keine kommerzielle Nutzung–Keine Bearbeitung 2.5 Schweiz” lizenziert. Die vollst¨ ndige Lizenz a kann unter creativecommons.org/licences/by-nc-nd/2.5/ch eingesehen werden.
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My gratitude goes to Prof. Dr. Matthias Hamburger who kindly accepted the faculty responsibility for my thesis.
I am grateful to Prof. Dr. Anna Seelig who kindly accepted to be the second reviewer of this thesis and I thank Prof. Dr. de Capitani for accepting to chair the examination.
My thanks go to the Senglet Stiftung for ﬁnancing my work.
I wish to thank my master student Veronika A. Eberle for her valuable work and for sharing a wonderful time.
I would like to thank Evi Bieler of Microscopy Center at Biozentrum for providing me with SEM images of my samples.
I would also like to thank Prof. Willem B. Stern and Prof. Christian de Capitani of the Department of Geosciences for allowing me to use the powder X-ray diffractometer and for their kind help.
My thanks go to the mechanical workshop for providing me with the made to measure tools for my modiﬁed dissolution system. My thanks also go to our laboratory assistant Stefan Winzap for his helpful presence.
ˇc My gratitude goes to Dr. Selma Sehi´. I was honored to build my thesis based on her valuable work and I am grateful for her continuous support. I further thank for the thermometric analyses performed at her company Bosnalijek.
ronqui, Dr. Sameh Abdel-Hamid, Dr. Firas Alshihabi, Branko Vrani´, Lizbeth Mart´nez, c ı Abdoulaye Theophile Sebgo, Nicolaos Gentis, Ylber Qusaj, Miki Yamashita, Yuya Yonezawa, Abhishek Kumar, and Sakine Tuncay for many fruitful discussions, exchange of laboratory and writing skills, and above all, for the many cheerful laughters and for sharing the unique “common spirit” of IPL.
I am deeply grateful to my parents and my sisters Anna, Rosa, and Odilia who have unconditionally supported me over all those years.
Above all, I thank my love, Adrian Lienhard, for his continuous support and for sharing many unforgettable moments.
Variability in raw materials presents a challenge for pharmaceutical companies. The varying physicochemical properties can critically inﬂuence drug release and bioavailability of the ﬁnal dosage form. Therefore, a strategy to control this variability is required. In this study the well-established antiepileptic drug carbamazepine (CBZ) was selected as the model drug as it presents one example where variability in raw materials has been linked to bioinequivalence and clinical failures. CBZ shows poor solubility, low potency, and a narrow therapeutic index. Furthermore, CBZ exhibits at least four polymorphic forms and it transforms into the less soluble CBZ dihydrate in water.
The purpose of this work was to study the impact of variability in CBZ samples of four different suppliers on the drug release and to suggest a strategy to deal with the sample variability. Thus, the CBZ samples were characterized at preformulation as well as at a formulation level.
Polymorphism and morphology of CBZ samples were analyzed by differential scanning calorimetry, X-ray powder diffraction, sieve analysis, and scanning electron microscopy. CBZ samples were characterized by a unidirectional dissolution method measuring disc intrinsic dissolution rate (DIDR) of CBZ raw material and initial drug release in presence of the tablet ﬁllers microcrystalline cellulose (MCC) and mannitol (30–90% drug load). Furthermore, CBZ samples were recrystallized in 1% polyvinylpyrrolidone ethanol solutions as an approach to reduce the sample variability. At the formulation level, a high-dose CBZ tablet was developed with the aim of a tablet formulation that is robust towards the variability in CBZ samples and that conforms to the USP requirements of CBZ tablets for immediate release. Therefore, the superdisintegrant crospovidone (CrosPVP) and the dry binder hydroxypropyl cellulose (HPC) were used, as both are reported to inhibit transformation to CBZ dihydrate. The tablet ﬁller was MCC.
All CBZ samples were of p-monoclinic form but differed in their polymorphic pu
rity, particle size, morphology, and intrinsic dissolution rate. The DIDR proﬁles showed high variability among the CBZ samples. Two inﬂection points could characterize individual transformation behavior of anhydrous CBZ to CBZ dihydrate. Presence of MCC reduced drug release variability. Recrystallizing CBZ resulted in strongly reduced variability in dissolution and tablet strength and the transformation to CBZ dihydrate was inhibited. However, particle size and morphology could not be controlled and drug release from binary mixtures with MCC presented deviation for one of the recrystallized CBZ samples. For the tablet formulation the optimal condition was with 6% HPC and 5% CrosPVP, where tablet properties of all CBZ samples were at least 70 N tablet hardness, less than 1 min disintegration, and within the USP requirements for drug release. Nonetheless, dissolution curves of the various CBZ samples differed. Excluding the additive sodium laurylsulfate required by the USP monograph and analyzing the optimized tablet formulation in water only, the dissolution curves of the various CBZ samples could not be distinguished anymore (ANOVA, p 0.05).
The impact of variability in CBZ raw materials on the drug release could be characterized by an individual transformation behavior to the CBZ dihydrate. The applied unidirectional dissolution method can be suggested as a straightforward monitoring tool in preformulation studies conforming to the basic tenet of quality by design of FDA’s PAT initiative. To allow a certain variability in CBZ raw materials, it is suggested to incorporate the excipients CrosPVP, HPC, and MCC into the design of a CBZ tablet formulation.
The strategy proposed of how to control the variability in CBZ samples includes the monitoring at preformulation level combined with the design of a robust tablet formulation.
CBZ re Recrystallized Carbamazepine CrosPVP Crospovidone = Cross-linked Polyvinylpyrrolidone DSC Differential Scanning Calorimetry DIDR Disk Intrinsic Dissolution Rate FDA Food and Drug Administration HPC Hydroxypropyl Cellulose HPMC Hydroxypropyl Methylcellulose IDR Intrinsic Dissolution Rate MANOVA Multivariate Analysis of Variance MCC Microcrystalline Cellulose PAT Process Analytical Technology
PEG Polyethylene Glycol PVP Povidone = Polyvinylpyrrolidone RH Relative Humidity rpm rounds per minute RSD Relative Standard Deviation SEM Scanning Electron Microscopy SLS Sodium Laurylsulfate STC Sodim Taurocholate SD Standard Deviation USP United States Pharmacopoeia XRPD X-ray Powder Diffractometry Chapter 1 Theoretical Introduction
1.1 Preformulation Studies Preformulation studies assess the physicochemical and biopharmaceutical properties of a drug candidate. These properties show whether the drug candidate can be formulated and they hint at potential problems in the drug performance and stability (Wells and Aulton, 2007). A thorough understanding of the drug properties is not only effective to reduce drug development time and cost but is also crucial to the quality and safety of the drug formulation. Therefore, preformulation is part of the ofﬁcial requirements for investigational new drugs and new drug applications by the Food and Drug Administration (FDA).
Also commercial requirements on drug delivery and dosage form can be a driving factor for preformulation studies (Carstensen, 2002).
An overview on the studies performed in preformulation is shown in Table 1.1. For the very ﬁrst physicochemical studies the synthesis of a drug is not at its ﬁnal scheme. After scale-up less impurities and more relevant data can be obtained, only then preformulation studies with higher precision make sense. Also studies on powder ﬂow, compaction properties, and excipient compatibility are important characteristics of a drug, however, they are often analyzed at a later stage as only small amounts (mg) of the new drug are available at earlier stages (Carstensen, 2002).
In case of abbreviated new drug applications (ANDAs), also called generics, the preformulation studies are less intensive (FDA, 2007). Nonetheless, physicochemical properties of a drug can vary with the source and this variation may lead to irregular dissolution behavior and clinical failures of the drug formulation (Wang et al., 1993; Meyer et al.,
2 CHAPTER 1. THEORETICAL INTRODUCTIONTable 1.1: Preformulation studies on a new chemical entity (NCE) according to Wells and Aulton (2007).
1992, 1998; Davidson, 1995; Jung et al., 1997; Lake et al., 1999; Mittapalli et al., 2008).
1.1.1 Biopharmaceutics Classiﬁcation System (BCS) Important guidance for the formulation scientist is the Biopharmaceutics Classiﬁcation System (BCS) proposed by Amidon et al. (1995). It allows classifying drugs according to their solubility and permeability (Figure 1.1). Furthermore, also the dose has to be considered and therefore the FDA’s Center of Drug Evaluation and Research (FDA CDER, 2009) deﬁned the limits of the cut-off values for the BCS classes including the drug dose. High solubility is deﬁned as highest dose strength soluble in 250 ml water over a pH range of 1.0–7.5 and high permeability is deﬁned as the absorption of 90% !
Figure 1.1: Biopharmaceutics Classiﬁcation System (BCS).
are discussed below (He, 2008):
• Class I: High solubility and high permeability of the drug, formulation for immediate drug release can be achieved without major challenge.
• Class II: An increasing number of the new chemical entities (NCEs) belong to this class of low solubility and high permeability, where the bioavailability is dissolution rate controlled. The challenge here is to overcome the low solubility.
The following options are available to improve solubility and thereby shift the drug from class II to I: (1) salt formation, (2) particle size reduction, e.g., nano particles, (3) metastable forms or amorphous state, (4) solid dispersion, (5) complexation, e.g., with cyclodextrins, (6) lipid based formulations, e.g., self-emulsifying drug
4 CHAPTER 1. THEORETICAL INTRODUCTIONdelivery systems, and (7) inhibition of precipitation / crystallization in the gastrointestinal tract (He, 2008).
• Class III: High solubility but low permeability of the drug, the oral route of administration can only be an option if prodrugs or permeability enhancers are available.
• Class IV: Solubility as well as permeability problems have to be addressed, it is most difﬁcult to achieve formulation from class IV drugs. Alternative delivery routes, such as intravenous administration are often the only solution. In general, poor permeability is rarely overcome by formulation approach.
The BCS has been reﬁned to classify drugs according to their stage of development (Papadopoulou et al., 2008). Whereas new chemical entities can be classiﬁed based on the solubility-dose ratio and permeability estimates, marketed drugs can be classiﬁed by mean dissolution time (MDT) and mean permeation time (MPT) of the gastrointestinal wall. Zakeri-Milani et al. (2009) were able to classify drugs according to the BCS by intrinsic dissolution rate, which is much faster obtained compared to the drug solubility.