Investigation of pico-litre inkjet printing for nano-gram scale solid form screening of pharmaceuticals

Al-Hachami, Wathiq (2018) Investigation of pico-litre inkjet printing for nano-gram scale solid form screening of pharmaceuticals. PhD thesis, University of Nottingham.

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The tendency of the majority of active pharmaceutical ingredients (APIs) to exist in different solid forms with keeping their chemical structures is called polymorphism. This phenomenon has gained a lot of interest in the pharmaceutical industry, hoping to avoid producing unexpected transformations of compounds during and after synthesis. The optimal way to avoid that is to subject the API, at the early stage of development, under various conditions in order to obtain an elegant (safe, effective, and stable) drug for the next formulation step. The aim of this thesis was to investigate some factors that affect the appearance of different polymorphs during screening of some APIs.

Four model drugs were selected: paracetamol; carbamazepine; mefenamic acid; and flufenamic acid. All have been well-characterised previously in terms of solid-state forms.

Piezoelectric, or 2D inkjet printing technique was used as a main technique in fabrication of nanoarrays of APIs onto predefined design on a solid tunable substrates because of its ability to control the delivered quantities of the the printed materials accurately, without any direct contact with the used substrate that may cause a sample cross-contamination. Light optical microscope was used to investigate the behaviour of the printed droplets during and after solvent evaporation and turn to dried spots, and to confirm the crystalline state of some spots by using the polarised light in the same microscope. Raman spectroscopy at low-wavenumber, or phonon region (40-400 cm-1) was used for the first time to identify the resulted polymorphs after the printing process as its ability to probe the alterations that happen in the molecular skeleton inside the crystal lattice , in addition to molecular region (400-1800 cm-1) to analyse the resulting spots.

In chapter three, the piezoelectric inkjet printing technique was successfully used for the first time to miniaturise, screen, and study the stability of the APIs at nano quantities in the range of (1-500 ng), about six-ordered magnification less than the reported studies. It was found that the variation in the printed quantities can produce different states and polymorphs. Stability with time was also studied for all the printed samples and it was noticed the variation in time for some printed drugs to convert from solid amorphous to crystalline state.

In chapter four, the advantage of the ability of the gold-coated slide to undergo further chemical modifications was exploited to create new substrates. Chemical modification of the gold substrates was carried out by treating them with two types of thiols to form self-assembly monolayers (SAMs) and use them as substrates in polymorph screening of some APIs. The new prepared SAMs were examined by preliminary tests like atomic force microscope (AFM) and water contact angle (WCA) measurements to investigate the texture of the new substrates before using them in printing process. It was found that changing the chemical structure of the substrate can lead to different polymorphs.

In chapter five, an attempt to create highly hydrophobic substrates was done to investigate whether it can affect the propensity of APIs for polymorphism. Fluorinated compounds were used in this chapter as they are considered more hydrophobic than the substrates used in the previous part of the work

The effect of the fluorinated substrates on appearance of new polymorphs was studied. Two fluorinated compounds were selected for preparation of high-water repellent surfaces and using them as substrates as they have the ability to limit the spreading of the printed droplets of the API, and allow the molecules to be constructed layer by layer and form a condense spot. The new fluorinated substrates were examined before using them in printing, and they exhibited high WCA. Another FLUF polymorph (VI) was investigated in addition to the two reference (I and III) polymorphs used in FLUF polymorphic screening. It was found that the intensity of the Raman peaks of the printed spots of APIs was good and clear to recognise when using fluorinated SAMs as a substrate, while the fluorinated substrate prepared from Flutec LE15 exhibited fluorescence effect due to the interactions between the glass and the drug’s spot spectrum.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Burley, Jonathan
Alexander, Morgan
Keywords: Polymorphism, Solid form screening, Inkjet printing technique, Raman spectroscopy
Subjects: R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 52031
Depositing User: Al-Hachami, Wathiq
Date Deposited: 31 Aug 2018 11:02
Last Modified: 01 Sep 2018 10:15

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