The role of anomeric content of lactose on the chemical stability and quality of tablets

Abstract

Lactose is an excipient that is present in more than 50% of all tablets. Although generally regarded as safe (GRAS), lactose is an isomeric compound that has been shown to undergo epimerisation previously. The epimerisation process of this reducing sugar was not investigated nor characterised in solid-state with the potential effect towards the stability of finished pharmaceutical products (FPP). Therefore, the aim of this project was to characterise the epimerisation process of lactose and investigate the effect of anomeric composition of lactose on the stability, quality and performance of tablets. H1NMR and DSC were used to monitor and measure the anomeric content of lactose samples during thermal analysis. The chemical stability of α lactose monohydrate was found to suffer epimerisation in solid-state post water-loss, reaching 11.6 ±0.9% β-anomer. This was supported by optical DSC and NMR that showed no thermal desorption. In accordance with ICH accelerated stability guidelines for storage (40°C/75% RH), epimerisation was found with β-lactose powder stored for 6 months to reach 96.1 and 3.9 ±0.3% α/β from 13.5% α. Lactose solid-state epimerisation kinetics was found to be zero-order with a shelf-life of 4.55 days. This resulted in the production and characterisation of ranging anomeric lactose content (50.2 and 79.5% α-anomer) from 35 and 60 days of ICH storage (40°C/75% RH). A novel DSC quality control method was developed to measure the anomeric content with LOD and LOQ of 13 and 19.8%, respectively. Promethazine HCL (PMZ) and anomeric ranges of lactose were formulated into tablets and stress tested. The HPLC results exhibited degradation with tablets manufactured with 50.2% α lactose while LC-MS identified 10-isobutyl-10H-phenothiazine and 10-methyl-10H-phenothiazine as the degradation products produced from tablets with epimerised lactose. Ranging anomeric content were also used to manufacture tablets that were physically tested (in accordance with the BP). Hardness data showed an increase in crushing strength for tablets compromising of 79.5% α compared to tablets produced with β lactose powders The disintegration time of tablets containing 79.5 % α was 27 s compared to the starting material (β lactose) of 220 s. Also, the dissolution data of acetylsalicylic acid (ASA) revealed higher rate of drug release from tablets compromising of 50.2 and 79.5 % α lactose, compared to tablets formulated with β lactose as received (T90 values being 80, 60 and 91 min, respectively). To conclude, the PhD showed novelty in; 1) Discovery of heat induced solid-state epimerisation; 2) Epimerisation recorded at ICH storage conditions; 3) Anomeric ratios causing chemical instability of PMZ at forced degradation (that was not recorded with feeding material) and 4) A new finding on the effect of anomers on the tablets’ drug (ASA) release rate, where an increased α anomer of lactose causes higher dissolution rate.

Date of Award	1 Jun 2024
Original language	English
Awarding Institution	King's College London
Supervisor	Paul Royall (Supervisor) & Andrew Chan (Supervisor)