Freezing process optimisation of pharmaceutical formulations for freeze drying

The body of work presented in this thesis are in three main parts: [1] the effect of ultrasound on freezing events of ionic systems, [2] the importance of formulation osmolality in freeze drying, and [3] a novel system for increasing primary freeze drying rate. Chapter 4 briefly presents the work on method optimisation, which is still very much in its infancy. Aspects of freezing such as nucleation and ice crystal growth are strongly related with ice crystal morphology; however, the ice nucleation process typically occurs in a random, non-deterministic and spontaneous manner. In view of this, ultrasound, an emerging application in pharmaceutical sciences, has been applied to aid in the acceleration of nucleation and shorten the freezing process. The research presented in this thesis aimed to study the effect of sonication on nucleation events in ionic solutions, and more importantly how sonication impacts on the freezing process. This work confirmed that nucleation does occur in a random manner. It also showed that ultrasonication aids acceleration of the ice nucleation process and increases the freezing rate of a solution. Cryopreservation of animal sperm is an important aspect of breeding in animal science especially for endangered species. In order for sperm cryopreservation to be successful, cryoprotectants as well as semen extenders are used. One of the factors allowing semen preservation media to be optimum is the osmolality of the semen extenders used. Although preservation of animal sperm has no relation with freeze drying of pharmaceuticals, it was used in this thesis to make a case for considering the osmolality of a formulation (prepared for freeze drying) as a factor for conferring protein protection against the stresses of freeze drying. The osmolalities of some common solutes (mostly sugars) used in freeze drying were determined (molal concentration from 0.1m to 1.2m). Preliminary investigation on the osmolality and osmotic coefficients of common solutes were carried out. It was observed that the osmotic coefficient trend for the sugars analysed could be grouped based on the types of sugar they are. The trends observed show the need for further studies to be carried out with osmolality and to determine how it may be of importance to protein or API protection during freeze drying processes. Primary drying is usually the longest part of the freeze drying process, and primary drying times lasting days or even weeks are not uncommon; however, longer primary drying times lead to longer freeze drying cycles, and consequently increased production costs. Much work has been done previously by others using different processes (such as annealing) in order to improve primary drying times; however, these do not come without drawbacks. A novel system involving the formation of a frozen vial system which results in the creation of a void between the formulation and the inside wall of a vial has been devised to increase the primary freeze drying rate of formulations without product damage. Although the work is not nearly complete, it has been shown that it is possible to improve and increase the primary drying rate of formulations without making any modifications to existing formulations, changing storage vials, or increasing the surface area of freeze dryer shelves.

Short cycle times for cost-efficient processing in lyophilized formulations

Pharmaceutical scientists who bulk freeze dry need to foremost identify what quality factors are of a priority during cycle development since the economics of freeze-drying do not allow for both the cost-efficient production and the ability to obtain the highest quality score across all quality factors. Consider; morphology, activity, dissolution, long-term storage, packaging and cost.

Formulations thermosensibles à base de chitosan pour la libération prolongée de médicaments

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Étude de l'efficacité pharmacologique de formulations d'oligonucléotides antisens pour cibler la P70S6 kinase suite à l'administration d'endothéline in vivo

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Formulations thermosensibles à base de chitosan pour la libération prolongée de médicaments

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Étude de l'efficacité pharmacologique de formulations d'oligonucléotides antisens pour cibler la P70S6 kinase suite à l'administration d'endothéline in vivo

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Robust scenario formulations for strategic supply chain optimization under uncertainty

Strategic supply chain optimization (SCO) problems are often modelled as a two-stage optimization problem, in which the first-stage variables represent decisions on the development of the supply chain and the second-stage variables represent decisions on the operations of the supply chain. When uncertainty is explicitly considered, the problem becomes an intractable infinite-dimensional optimization problem, which is usually solved approximately via a scenario or a robust approach. This paper proposes a novel synergy of the scenario and robust approaches for strategic SCO under uncertainty. Two formulations are developed, namely, naïve robust scenario formulation and affinely adjustable robust scenario formulation. It is shown that both formulations can be reformulated into tractable deterministic optimization problems if the uncertainty is bounded with the infinity-norm, and the uncertain equality constraints can be reformulated into deterministic constraints without assumption of the uncertainty region. Case studies of a classical farm planning problem and an energy and bioproduct SCO problem demonstrate the advantages of the proposed formulations over the classical scenario formulation. The proposed formulations not only can generate solutions with guaranteed feasibility or indicate infeasibility of a problem, but also can achieve optimal expected economic performance with smaller numbers of scenarios.

Extended formulations, nonnegative factorizations, and randomized communication protocols

An extended formulation of a polyhedron P is a linear description of a polyhedron Q together with a linear map π such that π(Q)=P. These objects are of fundamental importance in polyhedral combinatorics and optimization theory, and the subject of a number of studies. Yannakakis’ factorization theorem (Yannakakis in J Comput Syst Sci 43(3):441–466, 1991) provides a surprising connection between extended formulations and communication complexity, showing that the smallest size of an extended formulation of $$P$$P equals the nonnegative rank of its slack matrix S. Moreover, Yannakakis also shows that the nonnegative rank of S is at most 2^c, where c is the complexity of any deterministic protocol computing S. In this paper, we show that the latter result can be strengthened when we allow protocols to be randomized. In particular, we prove that the base-2 logarithm of the nonnegative rank of any nonnegative matrix equals the minimum complexity of a randomized communication protocol computing the matrix in expectation. Using Yannakakis’ factorization theorem, this implies that the base-2 logarithm of the smallest size of an extended formulation of a polytope P equals the minimum complexity of a randomized communication protocol computing the slack matrix of P in expectation. We show that allowing randomization in the protocol can be crucial for obtaining small extended formulations. Specifically, we prove that for the spanning tree and perfect matching polytopes, small variance in the protocol forces large size in the extended formulation.

A Multi-Objective Approach for VNE: Problems using multiple ILP formulations

Network Virtualization is a key technology for the Future Internet, allowing the deployment of multiple independent virtual networks that use resources of the same basic infrastructure. An important challenge in the dynamic provision of virtual networks resides in the optimal allocation of physical resources (nodes and links) to requirements of virtual networks. This problem is known as Virtual Network Embedding (VNE). For the resolution of this problem, previous research has focused on designing algorithms based on the optimization of a single objective. On the contrary, in this work we present a multi-objective algorithm, called VNE-MO-ILP, for solving dynamic VNE problem, which calculates an approximation of the Pareto Front considering simultaneously resource utilization and load balancing. Experimental results show evidences that the proposed algorithm is better or at least comparable to a state-of-the-art algorithm. Two performance metrics were simultaneously evaluated: (i) Virtual Network Request Acceptance Ratio and (ii) Revenue/Cost Relation. The size of test networks used in the experiments shows that the proposed algorithm scales well in execution times, for networks of 84 nodes