Pharmaceutical product development is a complex and creative design process, that involves
many factors, many unknowns, many disciplines and has a multiple iterations and a long lifecycle.
In the development of pharmaceutical dosage forms, one of persistent challenges is
getting an early stability assessment providing an understanding of critical formulation and
process parameters. In depth and science based knowledge, whether to use one excipient or
another, or to apply one process before the other, could help shortening the process time and
as a consequence save the money which is one of the goals of pharmaceutical industry.
Pelletization processes are usually lengthy and expensive. Processing of a single batch may
sometimes require hours or even days to be completed, and it can result in a non-robust
process. Formulation of a stable delivery system for lansoprazole is extremely difficult.
Lansoprazole belongs to class II drugs of the Biopharmaceutical Classification System (BCS),
characterized by low solubility and high permeability. Furthermore, lansoprazole degrades in a
highly acidic and highly basic environment, and it is also unstable under conditions of high
temperature and also high humidity, with a decrease in the amount of lansoprazole and
discoloration of the material being noted on storage under such conditions Tetsuro et al., 1992.
Additionally, a strong pH-dependent solubility of the drug was observed. There is therefore a
need for a pharmaceutical delivery system which protects the active substance both during
storage as well as the passage through the stomach.
The aim of this study was on the one hand the multifactorial investigation of crucial parameters
involved in the stability of lansoprazole pellets focusing on the formulation parameters and
preparation technique and on the other hand application of Arrhenius equation as a comparative
technique in stability of pellets as a solid dosage form.
Firstly, thermal characterization of lansoprazole has been conducted in order to clarify the
differences reported in the literature and elucidate the reason of the uncommon behaviour when
different heating rates were applied. Combining a differential scanning calorimeter (DSC),
thermogravimetric analysis (TGA) and hot-stage microscopy (HSM) technique, the results
confirmed that the melting point depression at low heating rates was due to eutectic behavior of
the drug with its decomposition products formed at low heating rates. Even when the high
heating rates (30 and 40°C/min) were applied melting point of lansoprazole did not show
independence on the heating rate and difference in the melting point was 1°C. Combination of
different techniques and highly dynamic and standardized methods for determination of thermal
properties of decomposable substances should be used.
Series of experiments were devised to study the effects of various formulation and processing variables on preparation and the stability of lansoprazole in order to examine some of the precautions which can be taken to minimize the loss of activity. Lansoprazole pellets were prepared using two different pelletizing techniques, solution suspension layering in bottom spraying fluidized bed and direct pelletization in rotor processor. Firstly, in a solution suspension layering, influence of type of neutral pellet (sugar based and microcrystalline cellulose based), type of stabilizing agent (influence of neutral and weak basic microenvironmental pH), presence of protective HPMC coating, type of aqueous enteric polymer based on shellac or methacrylic acid copolymer (Marcoat 125® or Eudragit L30 D-55®) and the coating levels on surface morphology, porosity, dissolution and stability of enteric coated pellets containing acid-liable drug, was evaluated. Furthermore, the aim was to investigate the feasibility of rotary processor for preparing lansoprazole loaded pellets based on Balocel®, which is a pre-mixed excipient blend containing microcrystalline cellulose, lactose and sodium carboxymethyl cellulose. Since pelletization in fluidized bed rotary processor is a multivariable process and the final characteristics of produced pellets are affected by several factors, in order to achieve a controlled, robust process and to optimize desired pellet properties, experimental design has been applied using expert design system STAVEX. The most important process variables related to the geometric mean diameter of lansoprazole pellets and the moisture content at the end of liquid addition phase, according to the pre-experiments, included spray rate and rotor speed, while the most influential formulation variable was a level of drug load. The study revealed that even though the process has been optimized to obtain pellets of optimum size and shape, another crucial property of pellets, dissolution, was disregarded and was confounded by another factor which could not be controlled (inlet air humidity) and which was not included in the design. This led to a conclusion, that no matter how comprehensive pre-experimental part of the design is, screening design should be applied. Accelerated degradation, studying the temperature effects in the presence of moisture on the degradation rate constant of lansoprazole in pellets prepared using different pelletization techniques, has been applied. In order to obtain rapid degradation with science based screening approach, Arrhenius equation has been used as a screening and comparative technique to describe a breakdown of lansoprazole in a solid dosage form and it has proved to be helpful tool in obtaining information on the most important formulation parameters and the optimum formulation of lansoprazole pellets for stability. Solution suspension layering technique proved to be more controllable process and more advantageous in terms of pellets size, shape and stability, but more time consuming in comparison to the direct pelletization. Study has confirmed that the key mechanism in obtaining a stabile lansoprazole delivery system is not only suppression of proton attacks but also a limitation of its solubility in the moisture layer, since it was found that in the pellets, lansoprazole
degrades following apparent zero-order kinetics. With weak basic microenvironmental pH in the
pellets it was possible to keep the degradation and solubility of lansoprazole on a low level.
Sugar core stabilized lansoprazole in a way of incorporating the drug in the core forming a less
porous active layer on the surface, disabling a contact of water and the active substance.
Presence of the protective layer has been justified since it increased the stability of lansoprazole
acting as a physical barrier between the drug and the free carboxyl groups of enteric coating
polymer. Predicted shelf-lives of pellets on room temperature should be confirmed with the data
obtained in a real time stability testing under the same conditions of relative humidity
