There is great value to understanding the role that pharmaceutical solubilizing excipients (surfactants, solubilizers, precipitation inhibitors, and dispersing agents) have on the concentration of poorly water-soluble active pharmaceutical ingredients in biorelevant media. Surfactants, solubilizers, precipitation inhibitors, and dispersing agents, among others, can improve biorelevant concentrations, which can translate into improved dissolution and bioavailability of the drug substance. When properly deployed, high throughput experimentation can significantly increase the volume of data generated, while using far less drug substance, excipients, and media. These automated experiments provide deeper insight under a wider variety of conditions than what could previously be achieved though manual processes. As a result, sufficient data is generated to develop accurate drug absorption models, as well as data-driven statistical analyses which provide greater insight to the pharmaceutical scientist during the development and design of a drug product.
The investigations presented here determine how micelle formation and steric interaction have a favorable impact on the aqueous concentration of poorly water-soluble active pharmaceutical ingredients in water and in simulated gastric and intestinal fluids. Biopharmaceutical Classification System (BCS) Class II molecules are evaluated in these investigations. Several molecules presented focus on proprietary active pharmaceutical ingredients currently in development, yet others are well-known and widely published model substances, to include Ibuprofen as a weak acid, Cinnarizine as a weak base, and Griseofulvin as a neutral non-ionizable molecule.
The purpose of this research is discussed in Chapter 1, and provides a brief overview of the hypotheses, specific aims, rationale, and the background and significance of determining the effect that certain solubilizing excipients (surfactants, solubilizers, precipitation inhibitors, and dispersing agents) have on the concentration of poorly water-soluble active pharmaceutical ingredients (APIs) in biorelevant media using high throughput experimentation.
In Chapter 2, the critical micelle concentration (CMC) of sodium lauryl sulfate (SLS) in water, simulated gastric fluid (SGF), and fed state simulated intestinal fluid (FeSSIF) was experimentally determined in the presence of “model Compound X” and “ model Compound Y” using UV/Visible spectrophotometry at 25 °C. To enhance the understanding of SLS aggregation, high throughput experiments were designed to determine the effect of increasing levels of SLS on the concentration of both drug substances as individual agents and as a possible combination product. The spontaneous formation of SLS micelles was supported by the calculated negative values of the standard free energy of micellization. The high throughput data was used to develop simulated in-vivo drug dissolution and absorption models to predict, and verify, that the increased concentrations of drug in biorelevant media results in improved absorption. Varying the amount of SLS used in the high throughput experiments helps determine the ideal amount of surfactant to use in an oral solid dosage form.
In Chapter 3, the solubility enhancement, precipitation inhibition, and dissociation of a model cocrystal drug substance identified as “Compound B” was investigated in combination with SLS and hydroxypropyl methylcellulose (HPMC), primarily using high throughput automation platforms. With further confirmation from an intrinsic dissolution rate apparatus, it has been determined that the cocrystal is significantly more concentrated in the presence of SLS and HPMC in biorelevant media when compared to the parent form. The high throughput data demonstrates that cocrystal dissociation can be prevented for up to 4 hours in the intestinal portion of the gastrointestinal tract. The use of HPMC elevates drug concentrations into supersaturation that is maintained for up to 24 hours.
In the face of mounting challenges to select the right solubilizing excipients for solubility enhancement of poorly water-soluble active drug substance, a first-intent matrix for selecting solubilizing excipients has been developed for use in oral solid dosage formulation design and is presented in Chapter 4. High throughput experimentation was used to assess the impact of varying levels of eleven commonly used solubilizing excipients on the solubility enhancement of Ibuprofen, Cinnarizine, and Griseofulvin. Enhancement of drug concentrations by use of solubilizing excipients depends on the type of solubilizing agent, the amount of that excipient, and the pH of the medium.
The research presented here is significant as the introduction of a new approach that formulation scientists can use during the early stages of formulation development. Ultimately, a matrix is presented for selecting appropriate solubilizing excipients to improve concentrations of BCS Class II drugs in biorelevant media, which ultimately results in better dissolution and absorption rates in the patient. This first-intent matrix enables simplification of the early development process by accelerating formulation design and product development for first-time-in-human studies.
|Advisor:||Neau, Steven H.|
|Commitee:||Jonnalagadda, Sriramakamal, Campbell, Gossett, Schaefer, Frederick, Patel, Sarsvatkumar|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 82/8(E), Dissertation Abstracts International|
|Subjects:||Pharmaceutical sciences, Biochemistry, Medicine, Public health|
|Keywords:||Automated solubility, Critical micelle concentration, High-performance liquid chromatography, High throughput experimentation, Mechanistic modeling, Solubility enhancement, Water-soluble drugs|
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