Crystallization as a Tool for Controlling and Designing Properties of Pharmaceutical Solids

The ability to deliver the drug to the patient in a safe, efficacious and cost-effective manner depends largely on the physicochemical properties of the active pharmaceutical ingredient (API) in the solid state. In this context, crystallization is of critical importance in pharmaceutical industry, as it defines physical and powder properties of crystalline APIs. An improved knowledge of the various aspects of crystallization process is therefore needed. The overall goal of this thesis was to gain better understanding of the relationships between crystallization, solid-state form and properties of pharmaceutical solids with a focus on a crystal engineering approach to design technological properties of APIs. Specifically, solid-state properties of the crystalline forms of the model APIs, erythromycin A and baclofen, and the influence of solvent on their crystallization behavior were investigated. In addition, the physical phenomena associated with wet granulation and hot-melting processing of the model APIs were examined at the molecular level. Finally, the effect of crystal habit modification of a model API on its tabletting properties was evaluated. The thesis enabled the understanding of the relationship between the crystalline forms of the model APIs, which is of practical importance for solid-state control during processing and storage. Moreover, a new crystalline form, baclofen monohydrate, was discovered and characterized. Upon polymorph screening, erythromycin A demonstrated high solvate-forming propensity thus emphasizing the need for careful control of the solvent effects during formulation. The solvent compositions that yield the desirable crystalline form of erythromycin A were defined. Furthermore, new examples on solvent-mediated phase transformations taking place during wet granulation of baclofen and hot-melt processing of erythromycin A dihydrate with PEG 6000 are reported. Since solvent-mediated phase transformations involve the crystallization of a stable phase and hence affect the dissolution kinetics and possibly absorption of the API these transformations must be well documented. Finally, a controlled-crystallization method utilizing HPMC as a crystal habit modifier was developed for erythromycin A dihydrate. The crystals with modified habit were shown to posses improved compaction properties as compared with those of unmodified crystals. This result supports the idea of morphological crystal engineering as a tool for designing technological properties of APIs and is of utmost practical interest.

Valittujen makrolidien ominaisuudet ja niiden vaikutukset fermentoinnin jälkeiseen jatkokäsittelyyn

Työn kirjallisessa osuudessa tarkasteltiin makrolideja yleisellä tasolla keskittyen kahden makrolidin ominaisuuksiin molekyylitasolla. Näiden tautomerisoitumista käsitellään tuoden esiin sekä yhdisteiden rakenteelliset yhteneväisyydet ja eroavaisuudet että niiden vaikutukset yhdisteiden vaikutusmekanismiin ja metaboliaan. Kirjallisessa osuudessa perehdyttiin myös makrolidien biosynteesiin ja tuotantoprosessiin keskittyen downstream-prosessointiin ja erityisesti biosynteesistä peräisin oleviin epäpuhtauksiin. Lisäksi kirjallisessa osuudessa käsiteltiin argentaatiokromatografian perusteita. Kokeellisessa osuudessa yhdelle makrolidille kehitettiin argentaatiokromatografiaan perustuva puhdistusmenetelmä. Perinteisillä kromatografisilla menetelmillä yhdistettä ei voida puhdistaa kaikista sen epäpuhtauksista. Makrolidin puhtaus argentaatiokromatografian jälkeen oli 98,6 %. Lisäksi kehitettiin uusi kiteytysmenetlmä, jossa yhdiste kiteytettiin anhydridina tavanomaisen monohydraattimuodon sijasta. Makrolidin analysointiin kehitettiin HPLC-menetelmä, joka validoitiin ICH:n ohjeiden mukaisesti. Yhditeen tautomeerimuodot ja siinä esiintyvät epäpuhtaudet tutkittiin käyttäen LC/MS-analyysia. Yhden epäpuhtauden rakenne varmistettiin eristämisen jälkeen NMR:n avulla. Saatavilla olevien tietojen mukaan yhdisteen tulkittuja NMRspektrejä ei ole julkaistu. Lisäksi aiemmin tuntematon epäpuhtaus identifioitiin perustuen retentioaikaan ja MS-analyysiin.

Characterization and evaluation of melibiose as novel excipient in tablet compaction

Lactose is probably the most used tablet excipient in the field of pharmacy. Although lactose is thoroughly characterized and available in many different forms there is a need to find a replacer for lactose as a filler/binder in tablet formulations because it has some downsides. Melibiose is a relatively unknown disaccharide that has not been thoroughly characterized and not previously used as an excipient in tablets. Structurally melibiose is close to lactose as it is also formed from the same two monosaccharides, glucose and galactose. Aim of this research is to characterize and to study physicochemical properties of melibiose. Also the potential of melibiose to be used as pharmaceutical tablet excipient, even as a substitute for lactose is evaluated. Current knowledge about fundamentals of tableting and methods for determinating of deformation behavior and tabletability are reviewed. In this research Raman spectroscopy, X-ray powder diffraction (XRPD), near-infrared spectroscopy (NIR) and Fourier-transform infrared spectroscopy (FT-IR) were used to study differences between two melibiose batches purchased from two suppliers. In NIR and FT-IR measurements no difference between materials could be observed. XPRD and Raman however found differences between the two melibiose batches. Also the effects of moisture content and heating to material properties were studied and moisture content of materials seems to cause some differences. Thermal analytical methods, differential scanning calorimetry (DSC) and thermogravimetry (TG) were used to study thermal behaviour of melibiose and difference between materials was found. Other melibiose batch contains residual water which evaporates at higher temperatures causing the differences in thermal behaviour. Scanning electron microscopy images were used to evaluate particle size, particle shape and morphology. Bulk, tapped and true densities and flow properties of melibiose was measured. Particle size of the melibiose batches are quite different resulting causing differences in the flowability. Instrumented tableting machine and compression simulator were used to evaluate tableting properties of melbiose compared to α-lactose monohydrate. Heckel analysis and strain-rate sensitivity index were used to determine deformation mechanism of melibiose monohydrate in relation to α–lactose monohydrate during compaction. Melibiose seems to have similar deformation behaviour than α-lactose monohydrate. Melibiose is most likely fragmenting material. Melibiose has better compactibility than α – lactose monohydrate as it produces tablets with higher tensile strength with similar compression pressures. More compression studies are however needed to confirm these results because limitations of this study.