Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co-Crystals.

Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry-X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.

Polymorphic Phase Transitions in Carbamazepine and 10,11-Dihydrocarbamazepine.

Temperature-induced phase transitions in carbamazepine (CBZ) and 10,11-dihydrocarbamazepine (DHC) were studied by simultaneous differential scanning calorimetry-X-ray diffraction in this work. The transitions generally involve a transitional melt phase which is quickly followed by recrystallisation. The expansions of the unit cell as a function of temperature could be quantified and allow us to determine a directional order of stability in relation to the lattice constants. Dihydrocarbamazepine form II undergoes a conversion to form I by a localised melt phase. Carbamazepine (CBZ) form IV converts to form I at 182 °C, again by a localised intermediate melt phase. CBZ form II converted to form I at 119 °C by a pathway that appears to have included some melting, and form III underwent a part melt-recrystallisation and a part sublimation-recrystallisation to form I.

Simultaneous Differential Scanning Calorimetry-Synchrotron X-ray Powder Diffraction: A Powerful Technique for Physical Form Characterization in Pharmaceutical Materials.

We report a powerful new technique: hyphenating synchrotron X-ray powder diffraction (XRD) with differential scanning calorimetry (DSC). This is achieved with a simple modification to a standard laboratory DSC instrument, in contrast to previous reports which have involved extensive and complex modifications to a DSC to mount it in the synchrotron beam. The high-energy X-rays of the synchrotron permit the recording of powder diffraction patterns in as little as 2 s, meaning that thermally induced phase changes can be accurately quantified and additional insight on the nature of phase transitions obtained. Such detailed knowledge cannot be gained from existing laboratory XRD instruments, since much longer collection times are required. We demonstrate the power of our approach with two model systems, glutaric acid and sulfathiazole, both of which show enantiotropic polymorphism. The phase transformations between the low and high temperature polymorphs are revealed to be direct solid-solid processes, and sequential refinement against the diffraction patterns obtained permits phase fractions at each temperature to be calculated and unit cell parameters to be accurately quantified as a function of temperature. The combination of XRD and DSC has further allowed us to identify mixtures of phases which appeared phase-pure by DSC.

Ink-jet printing versus solvent casting to prepare oral films: Effect on mechanical properties and physical stability.

The aim of this work was to compare and contrast the mechanical properties and physical stabilities of oral films prepared with either thermal ink-jet printing (TIJP) or solvent casting (SC). Clonidine hydrochloride was selected as a model drug because of its low therapeutic dose and films were prepared using cellulose polymers. Mechanical testing showed that the printed films had Young's moduli and tensile strength values similar to the free film, while casted films were significantly more brittle. The drug also appeared to crystallize out of casted films during stress testing whereas printed films remained unchanged. The dissolution behavior of printed and cast films were similar, because of the rapid disintegration of the polymer. The conclusion is that printing resulted in a better film than casting because the drug resided on the film, rather than in the film where it could exert a plasticizing effect.

3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets.

The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4-ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug-loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5-ASA. Significant thermal degradation of the active 4-ASA (50%) occurred during printing, however, indicating that the method may not be appropriate for drugs when printing at high temperatures exceeding those of the degradation point. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the formulated blends confirmed these findings while highlighting the potential of thermal analytical techniques to anticipate drug degradation issues in the 3D printing process. The results of the dissolution tests conducted in modified Hank's bicarbonate buffer showed that release profiles for both drugs were dependent on both the drug itself and on the infill percentage of the tablet. Our work here demonstrates the potential role of FDM 3DP as an efficient and low-cost alternative method of manufacturing individually tailored oral drug dosage, and also for production of modified-release formulations.

Fused-filament 3D printing (3DP) for fabrication of tablets.

The use of fused-filament 3D printing (FF 3DP) to fabricate individual tablets is demonstrated. The technology permits the manufacture of tablets containing drug doses tailored to individual patients, or to fabrication of tablets with specific drug-release profiles. Commercially produced polyvinyl alcohol (PVA) filament was loaded with a model drug (fluorescein) by swelling of the polymer in ethanolic drug solution. A final drug-loading of 0.29% w/w was achieved. Tablets of PVA/fluorescein (10 mm diameter) were printed using a 3D printer. It was found that changing the degree of infill percentage in the printer software varied the weight and volume of the printed tablets. The tablets were mechanically strong and no significant thermal degradation of the active occurred during printing. Dissolution tests were conducted in modified Hank's buffer. The results showed release profiles were dependent on the infill percentage used to print the tablet. The study indicates that FF 3DP has the potential to offer a new solution for fabricating personalized-dose medicines or unit dosage forms with controlled-release profiles. In addition, the low cost of FDM printers means the paradigm of extemporaneous or point-of-use manufacture of personalized-dose tablets is both feasible and attainable.

In vitro characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying.

Thermal ink-jet spray freeze-drying (TIJ-SFD) was used to produce inhalable particles of terbutaline sulphate, the aerosolisation properties of which were compared to the commercial Bricanyl formulation. Scanning electron micrograph images showed the particles to be spherical, highly porous and suitable for aerosolisation from a simple, capsule-based dry-powder device (Cyclohaler) without the need for additional excipients. Particle size was dependent upon the concentration of solution jetted, as well as the distance between the print head and the surface of the liquid nitrogen. Starting with a 5% (w/v) solution and maintaining this distance at 3cm produced spherical, porous particles of volume median diameter (VMD) 14.1 ± 0.8 µm and mass median aerodynamic diameter (MMAD) 4.0 ± 0.6 µm. The fine particle fraction (proportion of aerosol with MMAD ≤ 4.46 µm) was 22.9 ± 3.3%, which compared favourably with that of the marketed dry powder inhaler formulation of terbutaline (Bricanyl Turbohaler; 25.7 ± 3.8%), tested under the same conditions. These findings show that TIJ-SFD is a useful tool to predict the viability of a DPI formulation during preformulation physicochemical characterisation.

Quantifying crystallisation rates of amorphous pharmaceuticals with dynamic mechanical analysis (DMA).

One of the stability concerns for amorphous pharmaceuticals is phase transformation to a crystalline form. Since conversion from an amorphous matrix to a crystalline lattice should result in a change in mechanical modulus of the material dynamic mechanical analysis (DMA) offers potential as a stability-indicating assay for what are often complex formulations. Amorphous indomethacin glasses were used as model samples. Pockets made of a metal weave allowed the glass to be mounted in the instrument while ensuring exposure to RH. Crystallisation was manifest as an increase in the storage modulus signal with time. Conversion of the data to fraction crystallisation allowed quantitative determination of the rate and mechanism of crystallisation by application of the Urbanovici-Segal model. Rates of crystallisation were seen to increase with temperature and humidity while temperature and humidity affected the mechanism of crystallisation. High temperature and humidity resulted in three dimensional crystal growth. Reducing the humidity caused a switch in mechanism to growth from edges. Reducing temperature resulted in a mixed mechanism of growth from surfaces and edges. The DMA was also sensitive to crystallisation of phenobarbital sodium formulated in an oral film, but quantitative analysis was not possible as the onset of crystallisation was not recorded.

Preparation of personalized-dose salbutamol sulphate oral films with thermal ink-jet printing.

PURPOSE: To evaluate the use of thermal ink-jetting as a method for dosing drugs onto oral films. METHODS: A Hewlett-Packard printer cartridge was modified so that aqueous drug solutions replaced the ink. The performance of the printer as a function of print solution viscosity and surface tension was determined; viscosities between 1.1 and 1.5 mm(2) s(-1) were found to be optimal, while surface tension did not affect deposition. A calibration curve for salbutamol sulphate was prepared, which demonstrated drug deposition onto an acetate film varied linearly with concentration (r(2) = 0.9992). The printer was then used to deposit salbutamol sulphate onto an oral film made of potato starch. RESULTS: It was found that when doses were deposited in a single pass under the print head, then the measured dose was in good agreement with the theoretical dose. With multiple passes the measured dose was always significantly less than the theoretical dose. It is proposed that the losses arise from erosion of the printed layer by shearing forces during paper handling. The losses were predictable, and the variance in dose deposited was always less than the BP limits for tablet and oral syrup salbutamol sulphate preparations. CONCLUSIONS: TIJ printing offers a rapid method for extemporaneous preparation of personalized-dose medicines.

Characterisation of paracetamol form III with rapid-heating DSC.

Form III is the most unstable polymorph of paracetamol discovered and has not been fully characterized. Its instability in air means that it must be formed in situ in whichever instrument is used for analysis and even its melting point is the subject of discussion, because it undergoes a solid-solid conversion to form II when heated. The recent development of rapid-heat differential scanning calorimetry (RHDSC), which offers heating rates up to 2000 degrees C/min, provides a new opportunity to characterize unstable polymorphs because of the likelihood that form changes can be inhibited at higher heating rates. Hence the specific aim of this work was to use RHDSC to isolate and characterize paracetamol form III. Form III was prepared from the glass by holding isothermally at 113 degrees C for 2 min. Upon heating at slow scan rates (up to 300 degrees C min(-1)) a solid-solid transition to form II at ca. 120 degrees C was seen, followed by melting of form II at 156 degrees C. At heating rates of 400 degrees C min(-1) and higher, the solid-solid transition was absent and two endotherms were observed; the form II melt at 156 degrees C and a new, lower temperature endotherm at 143 degrees C. We ascribe the transition at 143 degrees C to the melting of form III. The form II melt was present in all experiments, irrespective of heating rate; thus we presume the paracetamol crystallizes to a mixture of forms II and III during preparation, indicative again of the unstable nature of form III. Experiments conducted with a crystal growth modifier (hydroxypropylmethylcellulose, HPMC) showed that increasing the HPMC molecular mass, or increasing the HPMC:paracetamol ratio, resulted in a concomitant increase in the form III peak, relative to the form II peak, which supports the hypothesis that the sample coexisted in both forms prior to crystallization.