(572d) Paliperidone: In Vitro Controlled Release from Long-Acting Prodrug Depot Suspension | AIChE

(572d) Paliperidone: In Vitro Controlled Release from Long-Acting Prodrug Depot Suspension


Sonntag, E. - Presenter, University of Chemistry and Technology Prague
Kolar, J., UCT Prague
Št?pánek, F., University of Chemistry and Technology Prague
One of the main goals of formulation scientists in the last several years is to ensure the delivery of BCS II and IV drugs (90% of all pipeline drugs [1]) at a reasonable rate and extent of bioavailability[2]. A possibility to overcome the negative clinical effects caused by poor water solubility is to increase the surface area, solubility, and wettability of powder drug particles by particle size reduction[3]. This trend of shifting pharmaceutical formulations to an ever-smaller scale has led to micro- and nano-formulations, such as intramuscular depot suspensions. These have a number of advantages over conventional oral dosage forms, including increased bioavailability, sustained/controlled drug release over months and the ability to maintain drug concentrations within the therapeutic range for a long time period. In particular, these benefits contribute to increasing patients' adherence to the pharmacotherapy, which is currently a frequently mentioned issue. It has been estimated that the cost to the US health care system in 2012 caused by patient nonadherence was about $200 billion[4].

The present work is focused on the intramuscular prodrug (paliperidone palmitate) depot nano-suspension, which is used in common practice as an intramuscular long-acting medication for schizophrenia treatment. Although this form has many advantages over the previous oral dosage form (sustained release, improvement of patients' adherence and quality of life), its disadvantage is the lack of IVIVC correlations and the absence of a detailed description of the parent drug (paliperidone) release mechanism from the drug formulation. The lack of IVIVC studies compared to conventional oral dosage forms is a general problem with depot formulations development, and a major barrier to their widespread use [5]. This, together with a lack of understanding of the in vivo release mechanism, often leads, in a generic drug development of such formulations, to the success in dissolution testing followed by failure in bioequivalence evaluation, which causes considerable time and financial losses.

The result of this work is an experimentally validated mathematical model describing the in vitro release of paliperidone from a nano-suspension of paliperidone palmitate (prodrug). The mechanism of paliperidone in vitro release is a reactive dissolution, i.e., dissolution of solid particles of paliperidone palmitate to the surrounding medium followed by conversion to paliperidone in the liquid phase. This mechanism mimics the in vivo release process that takes place after the intramuscular administration, where at the injection site a depot of prodrug particles is formed, from which the prodrug gradually dissolves into the tissue fluid and is converted to the parent drug by naturally occurring enzymes. In contrast to conventional dissolution tests, the proposed reactive dissolution model thus reflects not only the solid paliperidone palmitate particles dissolution kinetics but also the kinetics of its subsequent conversion. Such model can thus serve as a springboard for subsequent IVIVC correlation development. In its current form, the model can solve two types of tasks. The first, called as the “forward problem”, is the prediction of the release profile of paliperidone based on the initial particle size distribution (PSD) of the suspension. The second, the so-called “inverse problem”, can predict the initial PSD that will lead to obtaining the desired release profile. Specifically, the ability to solve the inverse problem could be used in the suspension dosage forms formulation strategy, where particle size modification steps are usually included in manufacturing, but the relationship between PSD and drug release rate is typically determined experimentally and often covers only a limited subset of the parametric design space.

The mathematical model describes the physical dissolution from different particle size classes of the suspension by population balance equation (Randolph & Larson; 1971) coupled with Nernst-Brunner equation, which depicts the dissolution kinetics of isolated spherical crystal. The mass transfer coefficient in a stirred vessel containing the depot suspension was obtained from Sherwood number calculated on the basis of the correlation proposed by Armenante & Kirwan (1989) suitable for particles of the order of few micrometers. Reynolds number was determined from particle diameter, kinematic viscosity, and energy dissipation rate. The dissolution kinetics was supplemented with the kinetics of paliperidone palmitate hydrolysis to paliperidone, which was measured experimentally. In order to reduce the time required to perform the experimental part, the hydrolysis of paliperidone palmitate was performed with hydroxide and not with enzyme. The mechanism of the basic hydrolysis (SN2 nucleophilic substitution) is known from the literature and the rate constant of prodrug conversion was determined from the experimental data. Due to the basic environment (pH ~11), mild degradation of paliperidone was observed in the experiments, which is also included in the developed model. The solution of the inverse problem is based on the same equations, but the model works iteratively using the Nelder-Mead optimization algorithm in order to find such combination of individual size fractions in a multimodal PSD that minimizes the difference between the desired and actual release profiles.

To validate the model in terms of solving the forward problem, a custom dissolution apparatus was designed, consisting of a 250 mL glass vessel with controlled agitation and temperature maintenance. A dissolution medium was added to this vessel into which the paliperidone palmitate suspension was being dissolved. The dissolution medium contained a reagent (lithium hydroxide) which ensured the conversion of paliperidone palmitate to paliperidone in the liquid phase. Although the conversion of paliperidone palmitate in vivo takes place enzymatically, basic hydrolysis has been used, which can be carried out at higher temperatures (increasing and overall process rate), has a known mechanism and is less sensitive to environmental conditions. To measure the time evolution of the concentration of both substances, an HPLC (Agilent 1100) method was developed. The reliability and accuracy of the experimentally measured data were verified on the basis of criteria set by the ICH guidelines (CDER, US FDA).

Validation of the ability to solve the inverse problem has so far been performed on a different system than paliperidone, mainly in terms of time savings as paliperidone palmitate dissolution rate is very low. The experiments were performed with a suspension of potassium chloride (KCl) crystals. Because KCl dissolves very rapidly in aqueous media, the real-time dissolution kinetics is difficult to be measured. Therefore, the experiments were performed in a mixture of water and isopropanol (3:10 by volume), which slowed down the dissolution rate. The real-time measurements of PSD evolution and dissolution kinetics were performed in the flow cell of a static light scattering instrument (Horiba Partica LA-950). The flow cell served as a dissolution tank in which a conductometer (Mettler Toledo SG23) was inserted to measure the KCl concentration.


1. Benet, L., In EDAN, Leuven, Belgium, March 2017.

2. Lipp, R., Major advances in oral drug delivery over the past 15 years. American Pharmaceutical Review 2013, 16.

3. Subramaniam, B.; Rajewski, R. A.; Snavely, K., Pharmaceutical Processing with Supercritical Carbon Dioxide. Journal of Pharmaceutical Sciences 1997, 86 (8), 885-890

4. IMS Institute for Healthcare Informatics Avoidable costs in US health care. 2013

5. Chavda, V., et al. (2016). "In Vitro–In Vivo Correlation" Research & Reviews: A Journal of Drug Formulation, Development and Production