| dc.description.abstract | The thesis focuses on the use of different manufacturing techniques for the generation of
amorphous solid dispersions (ASDs) for the enhancement of the solubility of model compounds.
ASDs with hydrochlorothiazide (HCTZ) or simvastatin (SIM) were successfully manufactured via
spray drying (SD) and liquid antisolvent (LAS) co-precipitation (CP). The LAS CP resulted in the
generation of ASDs characterized by component ratios similar to the theoretical values. The novel
approach undertaken in this thesis related to the co-processing of materials in the lab-scale
chemical reactor with the use of organic solvents only to generate amorphous solid dispersions
(ASDs). Moreover, not only binary API-polymer systems were investigated, but also ternary API-
polymer-silica formulations, which were generated either from solutions or suspensions in the CP
process. The work carried out in this thesis incorporated all aspects of the pharmaceutical drug
development process for the CP technique on the laboratory scale. The impact of differences in
both API and excipients used were explored, with a diverse range of behaviours displayed by the
various co-precipitated API/polymer or API/polymer/silica combinations investigated, which were
compared to the equivalent spray-dried formulations. In particular, the effect of CP process
parameters on changes to the particle size distribution was investigated. In this thesis, the CP
process and feed parameters required for powder generation and the impact of the
manufacturing technique on the powder products, as well as the role excipients play on the final
product characteristics were studied.
All raw materials employed in this study were characterized, followed by the selection of CP
parameters. The preformulation studies demonstrated different melting temperatures (Tms), glass
transition temperatures (Tgs) and solubilities in organic and aqueous solvents for the two model
active pharmaceutical ingredients (APIs). The hydrophilic, polymeric excipients (Kollidon® VA 64
(PVP/VA) and Soluplus®) utilized were characterized by different Tgs (107 °C and 70 °C,
respectively) and have been successfully used in the production of ASDs by spray-drying. One of
the challenges associated with LAS CP relates to the potential different solubilities of formulation
components in the final mixture of solvents, in which the solids should have good solubility and
poor solubility (antisolvent), which might result in a disproportionate loss of one of the materials
from the co-precipitate product, limiting the robustness of the process. The feasibility of the LAS
CP process to be conducted with non-aqueous antisolvents and compounds with a high Tg
(HCTZ:117°C) or low Tg (SIM:35°C) was investigated.
The successful co-precipitation of ASDs at the screening stage (40 mL) enabled successful co-
precipitation at a larger scale (100 mL) with the same parameters for HCTZ-based systems and
with further optimized parameters for SIM-based systems. The SEM analysis of particles obtained
from precipitated slurries compared to filtered, vacuum-dried powders demonstrated changes in
the particle morphologies when additional unit operations were employed. Particle counts and
chord length distributions (CLD) were monitored in situ using a Focus Beam Reflectance
Measurement (FBRM) probe, and showed differences, depending on the API used, due to
different investigated process parameters, such as the type of a stirring device, mixing rate, type of
antisolvent, solvent to antisolvent ratio, antisolvent temperature, solvent addition rate, order of
solvents addition and other modifications of the process.
Binary (API with polymer) HCTZ-based and SIM-based ASDs were manufactured by SD and CP. The
influence of the manufacturing process as well as polymer type were studied for their impact on
product powder characteristics. Spray-dried and co-precipitated powders showed largely similar
Tgs for SIM-based systems, but different Tgs for HCTZ-based materials. Moreover, for both
methods, experimentally obtained Tgs were either lower or higher than theoretically estimated Tg
values by the Gordon-Taylor equation for SIM and HCTZ-based systems, respectively. However, Tg
differences did not have an impact on the physical stability of ASDs kept on storage at 75%
RH/25°C for one month, which all remained amorphous, regardless of the manufacturing method
used. This work highlights that, despite the suitability of both techniques for producing ASDs and
many similarities between the final critical quality attributes (CQAs) of the powders obtained, the
SD technique has many advantages over CP. Firstly, it can be viewed as a more environmentally
friendly approach due to the lower amounts of solvents which are required to be used per 1 g of
powder produced. Secondly, while both SD and CP techniques have the potential to be used in
continuous processing, CP requires more post-processing unit operations, such as filtration and
drying. However, powders produced by CP have a larger particle size, resulting in a better
flowability than powders produced by SD, although tablets prepared with CP-processed powders
had a lower mechanical strength. The work of this thesis also highlights the similarity in solubility
enhancement of ASDs prepared by CP and SD, relative to their respective crystalline materials.
The addition of silica as a third component and a co-precipitation processing aid to ASD
formulations addressed the challenges associated with the high stickiness of co-precipitates to the
vessel bottom and walls, which was observed on filtration. This behaviour impedes solvent
removal because it makes sample handling and spreading on the filter, which is meant to facilitate
solvent removal, difficult. By presenting two alternative methods of silica inclusion into the CP
process - either (A) suspended in the antisolvent (to which a feed solution of polymer and API is
added) or (B) added as a feed suspension (with API and polymer dissolved in the same liquid
feed), it was shown that the generation of ternary ASDs with similarly enhanced API solubilities,
relative to the crystalline material, can be achieved.
These studies also outlined several differences between the CP and SD methods in co-processing
all components of the formulation in one step. Similarly to binary API/polymer powders, ternary
dried co-precipitated systems were characterized by larger particle size and more irregular particle
shapes than ternary spray-dried materials. While only ternary SIM/Aerosil®200 CP systems
exhibited poorer flowability than the binary CP samples, ternary SD samples with Syloid®XDP 3050
and Aerosil®200 demonstrated significantly poorer flowability than SD binary materials. It was
shown that, in the case of both a high Tg API (HCTZ), which demonstrated (by FT-IR) intermolecular
interactions in ternary systems, and a low Tg API (SIM,) which did not demonstrate intermolecular
interactions in ternary systems, there were significant differences in the Tgs of ternary systems
between SD and CP-processed materials, especially in the case of SIM-based systems, as opposed
to binary SIM/polymer powders, dependent on the silica grade used.
The work conducted and presented in this thesis highlights an already well-established process in
the pharmaceutical industry, namely spray-drying, and a just-emerging technology, namely liquid
antisolvent co-precipitation, that can both be applied to ASD production. Both these methods
have the potential to be used in a continuous mode. However, the larger particle size favours CP as
a candidate for downstream tabletting processes involving direct compression, due to enhanced
flowability. While processing APIs with a high or low Tg is feasible by these two techniques, the
large solvent waste generated by the CP method should be taken into consideration when
selecting a process for large scale manufacture. | en |
