The making of liqui-pellet and liqui-tablet, the next generation oral dosage form

Lam, Matthew (2019) The making of liqui-pellet and liqui-tablet, the next generation oral dosage form. Doctoral thesis (PhD), University of Sussex.

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Abstract

The aim of the project is to use concept from liquisolid technology to improve dissolution rate, which is the rate limiting step for bioavailability for poorly water-soluble drug. This is a major challenge in the pharmaceutical industry. In fact, approximately 60% of drugs in the market are considered poorly soluble in gastrointestinal fluids, and around 40% of drugs in development are identified as poorly water-soluble; both of which is based on biopharmaceutical classification system (BCS). There are various other technologies with the same purpose of improving dissolution rate, however, liquisolid technology hold key advantages making it appealing to formulation scientist. These advantages include: simplistic approach (advance machinery and technique not required); cost effective; use green technology and excipient used are conventional and easily obtainable. Despite such appealing advantages, in reality liquisolid technology is hampered from being commercially used due to major drawbacks such as, inability to produce high dose drug without being too bulky for swallowing and poor flow property, which poses difficulty in manufacturing. This give rise to the invention of liqui-pellet and liqui-tablet in this project, which successfully overcome liquisolid drawbacks. These new dosage form can have high liquid load factor whilst achieving excellent flow property as well as maintaining acceptable weight for high dose drug.

Liqui-pellet stems from the combination of concept from liquisolid technology and pelletization technology. Poorly water-soluble API (active pharmaceutical ingrideint) such as, naproxen and hydrochlorothiazide (HCTZ) were used as the model API. Naproxen and HCTZ liqui-pellet were successfully made, including their optimized formulations. Some of these optimized formulations included effervescent agent (sodium bicarbonate), superdisintegrant and high specific surface area carrier (neusilin US2). This demonstrate that liqui-pellet is versatile for formulation design modification via addition of functional excipient/s whilst maintaining acceptable weight for swallowing. In fact, all formulation made was of acceptable weight for swallowing. Almost all of the formulations have relatively high liquid load factor whilst achieving excellent flowability, which has not been seen in liquisolid formulation before. Furthermore, the optimized naproxen was able to achieve remarkably rapid drug release rate of 100% in 20 min at an acidic pH of 1.2, which naproxen is known to be practically insoluble in. As for optimized HCTZ liqui-pellet, 100% drug release rate was achieved after 15 min at pH 1.2. Such rapid drug release rate is shown to be more superior than other technologies including liquisolid compact, solid dispersion and solid self-dispersing micelle when compared with other studies.

From liqui-pellet, the focus of the project shift to liqui-tablet, which in its simplest form is essentially compressed liqui-pellet. The aim is to explore the potential to diversify this new technology and to respond to the strong incentive for tablet dosage form (tablet being the most favored oral dosage form and more cost-effective than capsule). Naproxen liqui-tablet was successfully made, verifying liqui-tablet feasibility. The liqui-tablet was able to revert back to its multi-unit pellet system, which maintain the inherent advantages of liqui-pellet; but also, able to maintain the rapid drug dissolution rate.

The final investigation was to see if high dose liqui-tablet was feasible (ketoprofen 100mg). Ketoprofen 100mg liqui-tablet was successfully made, verifying its feasibility. Not only was it feasible, it also only weighed 483.8mg whilst having excellent to good precompressed flow property. This is a major advancement as it takes liquisolid concept into a commercially feasible direction for high dose drug, which has never been achieved in liquisolid formulation before.

Throughout the project, various other physicochemical properties were analyzed such as: flowability test; saturation solubility test; friability test; particle size analysis by sieve method; stereoscopic analysis; tablet hardness test; scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and stability test. In general, most formulation achieve good robustness and excellent flow properties with narrow size distribution, which is ideal for manufacturing and quality control test.

Overall, liqui-pellet and liqui-tablet have demonstrated itself a promising next generation oral dosage form with capability of remarkably rapid drug release, and array of advantages including versatility for formulation manipulation (i.e. addition of functional excipient/s), cost-effective, simple to produce, inherent advantages from liquisolid technology and inherent advantages from pelletization technology.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: H Social Sciences > HD Industries. Land use. Labour > HD9000 Special industries and trades > HD9665 Pharmaceutical industry
R Medicine > RS Pharmacy and materia medica > RS0153 Materia medica > RS0200 Pharmaceutical dosage forms
R Medicine > RS Pharmacy and materia medica > RS0153 Materia medica > RS0400 Pharmaceutical chemistry > RS0420 Drug design
Depositing User: Library Cataloguing
Date Deposited: 14 Feb 2019 09:33
Last Modified: 12 Oct 2022 09:32
URI: http://sro.sussex.ac.uk/id/eprint/81934

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