Pullulan is an exopolysaccharide secreted extracellularly by the black yeast-like fungi Aureobasidium pullulans. Due to an alpha-(1-->6) linked maltotriose repeat unit, which interferes with hydrogen bonding and crystallization, pullulan is completely water soluble unlike cellulose. It has also been tested and shown to possess non-toxic, biodegradable, non-mutagenic and non-carcinogenic properties. Chemical modification of polysaccharides to increased hydrophobicity and increase functionality has shown great promise in drug delivery systems. Particularly in amorphous solid dispersion (ASD) formulations, hydrophobicity increases miscibility with hydrophobic, crystalline drugs and carboxy functionality provides stabilization with drug moieties and well as pH specific release. Successful synthesis of cellulose w-carboxyalkanoates have been reported and showed great promise as ASD polymers based on their ability to retard the recrystallization of the HIV drug ritonavir and antibacterial clarithromycin. However, these cellulose derivatives have limitations due to their limited water solubility. Natural pullulan is water-soluble and modification with w-carboxyalkanoate groups would provide a unique set of derivatives with increased solubility therefore stronger polymer-drug interactions in solution. We have successfully prepared novel pullulan w-carboxyalkanoates, which exhibit good solubility in polar aprotic and polar protic solvents. All derivatives exhibit high thermal stability and most recorded high glass transition temperatures. Due to unknown impact of their three dimensional structure on miscibility and stabilization of drug against crystallization, each of these polymers possesses great potential for use in various drug delivery applications. / Master of Science

No description available.

<p>The symmetry requirements of both second harmonic generation (SHG) and triboluminescence (TL) provide outstanding selectivity to noncentrosymmetric crystals, leading to high signal to noise measurements of crystal growth and nucleation of active pharmaceutical ingredients (API) within amorphous solid dispersions (ASD) during accelerated stability testing. ASD formulations are becoming increasingly popular in the pharmaceutical industry due to their ability to address challenges associated with APIs that suffer from poor dissolution kinetics and low bioavailability as a result of low aqueous solubility. ASDs kinetically trap APIs into an amorphous state by dispersing the API molecules within a polymer matrix. The amorphous state of the API leads to an increase in apparent solubility, faster dissolution kinetics, and an increase in bioavailability. Both SHG and TL are used to quantitatively and qualitatively detect the crystal growth and nucleation within ASD formulations at the parts per million (ppm) regime. TL is the emission of light upon mechanical disruption of a piezoelectrically active crystal. Instrumentation was developed to rapidly determine the qualitative presence of crystals within nominally amorphous pharmaceutical materials in both powders and slurries. SHG was coupled with a controlled environment for <i>in situ</i> stability testing (CEiST) to enable <i>in situ</i> accelerated stability testing of ASDs. Single particle tracking enabled by the CEiST measurements provided insights into crystal growth rate distributions present due to local differences within the material. Accelerated stability testing monitored by <i>in situ</i> measurements increased the signal to noise in recovered nucleation and crystal growth rates by suppressing the Poisson noise normally present within conventional accelerated stability tests. The disparities between crystal growth and nucleation kinetics on the surface versus within bulk material were also investigated by single particle tracking and <i>in situ </i>measurements. Crystals were found to grow faster in the bulk compared to single crystals growing on the surface while total crystallinity was found to be higher on the surface due to radial growth habits of crystals on the surface compared to columnar growth within the bulk. To increase the throughput of the <i>in situ </i>measurements, a temperature and relative humidity array (TRHA) was developed. The TRHA utilizes a temperature gradient and many individual liquid wells to enable the use of a multitude of different conditions at the same time which can reduce time required to inform formulations design of stability information. </p>

The success of an amorphous solid dispersion (ASD) formulation, consisting of a homogeneous molecular dispersion of drug and polymer, relies on its ability to create and maintain a supersaturated solution. However, supersaturated solutions are metastable and prone to crystallization. In solution, crystals are expected to serve as a template for crystal growth, depleting achieved supersaturation. Thus, in an ASD product, ideally no crystallinity should be present. However, technical challenges exist in both processing and characterization to routinely ensure this is achieved. The presented studies follow the process design, characterization, and dissolution performance of hot melt extruded amorphous solid dispersions, seeking insight into the significance of critical quality attributes of resulting extrudates, namely residual crystallinity and thermal degradation.<div>Selection of hot melt extrusion (HME) processing conditions to prepare ASDs is governed by thermodynamic and kinetic attributes of the drug and polymer system. Mapping the temperature-composition phase diagram to HME processing conditions provides a processing design strategy to prevent residual crystallinity while simultaneously avoiding thermal degradation. Through processing temperatures below the drug’s melting point (Tm) and above the formulation critical temperature (Tc), fully amorphous systems could be generated if sufficient kinetics were provided. The utility of thermogravimetric analysis was critically examined for prediction of the chemical stability processing window for HME formulations.<br></div><div>For characterization and product performance characterization, residual crystalline content in HME ASDs can be anticipated and tailored to various levels. Several HME ASDs were characterized by a range of analytical techniques, highlighting the sensitivity of available techniques to qualitatively or quantitatively detect crystalline content (depending on limitations which stem from properties of the instrument or sample). Transmission electron microscopy (TEM) was found to identify low levels of crystallinity not observed by other technique and provide insight into crystal dissolution mechanisms. A defect-site driven dissolution and fragmentation model was suggested, and supported by a Monte Carlo simulation, underscoring that crystal defect sites, either intrinsic to the crystals or formed during processing, expedite dissolution rates and generation of new surfaces for dissolution.<br></div><div>Non-sink dissolution was performed for indomethacin/PVPVA HME ASD samples with residual crystallinity ranging from 0-25% crystalline content. Due to effective crystal growth inhibition by the polymer, crystals had little impact on dissolution performance. Achieved supersaturation was reduced approximately by the level of crystallinity present, i.e. a lost solubility advantage. These studies have significance for HME processing design and risk assessment of crystallinity within ASD formulations.<br></div>

Using various synthetic strategies, we designed several libraries of novel polysaccharide mixed ester derivatives for oral drug delivery applications. Cellulose and cellulose esters have been extensively studied and utilized for different applications such as separation membranes, sustainable plastics, and enteric coatings in oral drug delivery carriers. We sought to exploit the ring-opening of cyclic anhydrides, succinic and glutaric anhydride, to append ω-carboxyl groups to commercially available cellulose and cellulose ester substrates. We used scalable synthetic strategies and widely available and cheap reagents to show a proof-of-concept for the manufacturability of these different polymer derivatives. We incorporated different degrees of substitution of ω-carboxyl groups to impart a range of water solubility in these polymers. The derivatives displayed excellent <i>T</i>g values for ASD applications, adequate water solubility, and good amphiphilic properties. We designed very effective amorphous solid dispersion (ASD) oral drug delivery polymers that prevented recrystallization of felodipine for hours and had excellent congruent polymer-drug release from the formulation at 20% drug loading. During the ring-opening reactions of the cellulose derivatives with glutaric anhydride we discovered that crosslinking and gelation can occur, especially with cellulose and cellulose ester substrates with a high degree of substitution (DS) of hydroxy groups. We isolated and characterized these gelled products using rheology, and solid-state 1D and 2D NMR spectroscopy, to evaluate whether the gels are physical or chemical in nature and proposed a mechanism for gelation. We determined that the gels are mostly physical but can proceed to chemical crosslinking over time. We designed a library of cellulose ester derivatives, and we investigated their performance as amorphous solid dispersion (ASD) drug delivery vehicles for the lipophilic drug felodipine, through <i>in vitro</i> experiments. Aside from felodipine, many other active pharmaceutical ingredients (APIs) are also highly crystalline and poorly water-soluble. ASDs are used to disrupt the crystalline packing of these drugs through dispersing them in amorphous polymeric carriers, facilitating their water-solubility, and preventing their recrystallization. We showed that our polymers performed remarkably well in the <i>in vitro</i> studies and inhibited crystallization of model compound felodipine for several hours while providing optimal drug release, affording highly promising ASD polymers. If company formulators are unable to develop an effective oral-delivery carrier to prevent a drug from recrystallizing, then the drug cannot be tested in <i>in vivo</i> toxicology studies, and therefore cannot be brought to market because of its poor aqueous solubility and subsequent low bioavailability. To test the robustness of our polymers, we also performed <i>in vitro</i> ASD experiments at the pharmaceutical company AbbVie with their most rapidly crystallizing pipeline compounds, and several commercially available drugs (Compound A, axitinib, and ziprasidone). We demonstrated that our polymers could also prevent drug recrystallization with these rapid crystallizers, outperforming commercial polymers like FDA-approved hydroxypropyl methyl cellulose acetate succinate (HPMCAS (MF)), even at exceptionally high drug loading ratios of 40 times the concentration of polymer. α-1,3-Glucans are an emerging class of polysaccharides and are structurally different than cellulose due to their α (1→3) linkage versus the cellulose β (1→4) glycosidic linkage. We demonstrated that we could modify these derivatives using a variety of esterification strategies and TEMPO-mediated C6 selective oxidation, affording a myriad of different novel polymer products, some of which are structural analogs of the cellulose ester derivatives we previously created. The polymers had higher <i>T</i>g values than the cellulose ester polymers, which may be useful for applications where heat resistance is desired. In the future, we will screen some of these α-1,3-glucan derivatives with poorly water-soluble enzalutamide, posaconazole and celecoxib model drugs, to evaluate their crystallization inhibition properties and the influence of polymer morphology upon structure-property relationships. We expect that these synthetic polymer strategies will offer scalable routes to novel ASD polymers, which we demonstrated to be highly effective drug crystallization inhibitors against a variety of different hydrophobic pharmaceutical compounds. / Doctor of Philosophy / Polysaccharides are polymers comprised of many linked sugar molecules and are an incredibly abundant and renewable resource. They are found everywhere in nature such as the wood from trees, the shells of crabs, the exoskeletons of bugs, and the mushrooms that sprout in damp forests. The research in this dissertation focuses on the use and chemical modification of polysaccharides for designing new, polysaccharide-based oral drug delivery systems called amorphous solid dispersions (ASDs), which significantly aid in the solubility and bioavailability of important medications. We started with the chemical modification of cellulose, the most abundant plant polysaccharide on planet Earth, and previously modified commercial cellulose substrates (known as cellulose esters) to create novel polymers for ASDs. We successfully modified these polymers, characterized them, and evaluated their potential as oral drug delivery vehicles by formulating them with several different classes of potent drugs used to treat a variety of diseases such as hypertension and schizophrenia. We showed that our designed cellulose ester polymers kept these hydrophobic drugs water-soluble for long-enough so that they can be adequately absorbed in the human body through the gastrointestinal tract, significantly outperforming commercial polymers in many cases. During the chemical modification of the cellulose esters, we also observed that they were prone to form gels, and we investigated this gelation phenomena in more detail through rheometry, 1D and 2D solid-state nuclear magnetic resonance spectroscopy (similar in principle to the medical diagnostic method, magnetic resonance imaging or MRI). We discovered that these gels can be physically and/or chemically linked together, and that different gelation mechanisms can dominate depending on the polysaccharide substrate and the esterification reagent used. We extended our research to other polysaccharide derivatives called α-1,3-glucans, which can be sourced from fungi, and/or enzymatically synthesized in the lab. Using various synthetic esterification and oxidation chemical methods to functionalize this polysaccharide, we designed a library of entirely novel polymers with different physical structures relative to the cellulose ester polymers. The polymers displayed thermal properties that show promise in drug delivery vehicle applications and in applications where high heat resistance is required. Overall, we developed next-generation polymers for amorphous solid dispersion oral drug delivery applications. We displayed the versatility of using a select few chemistry strategies to create a variety of different polymers with very different physicochemical properties. We hope that this work will help researchers design sustainable, plant-based polymers for ASD applications and we hope to nurture future structure-function studies to improve ASD performance for the benefit of patients in need.

<p dir="ltr">Amorphous solid dispersions (ASDs) are being widely used as enabling formulations for poorly water soluble drugs. An ASD is a molecular level mixture of an amorphous drug and a polymer to form a single-phase homogeneous blend. The amorphous form of a drug provides a higher transient solubility compared to equilibrium crystalline solubility, whereby the presence of a polymer of appropriate properties aids in crystallization inhibition. Polymers also improve the release rate of the drug from the ASD relative to the release rate of neat amorphous drug, specifically for release regimens where both drug and polymer release congruently. Hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based ASDs tend to show congruent release of drug and polymer across multiple drug loadings, providing a significant dissolution improvement even beyond the amorphous solubility of a drug. Enteric polymers such as HPMCAS have been studied extensively in terms of enteric coated tablets but haven’t been explored in as much detail when molecularly dispersed with a drug as in case of ASDs. Literature shows not all ASDs are able to improve bioavailability of drugs. Such a failure to provide bioavailability advantage via certain ASDs could come from a randomized drug and polymer selection in the preformulation stage of drug product development which could fundamentally arise from the lack of understanding of the release mechanisms of ASDs. Given that HPMCAS is one of the most popularly used polymers for spray drying of ASDs in the pharmaceutical industry, investigating the release mechanisms of HPMCAS-based ASDs is critical. In this study, some of the key formulation design factors, such as drug-polymer interactions, different grades of polymer as well as dissolution media factors such as buffer capacity that impact the release performance of HPMCAS-based ASDs have been investigated. The results from this study are expected to contribute to the fundamental understanding of the failure mechanisms of HPMCAS-based ASDs, reducing empirical screening of drugs during the preformulation stage of the product development and enhance the success rate of ASDs.</p>

Over the past few decades, amorphous solid dispersions (ASDs) have been of great interest to pharmaceutical scientists to address bioavailability issues associated with poorly water-soluble drugs. ASDs consist of an active pharmaceutical ingredient (API) that is typically dispersed in an inert polymeric matrix. Despite promising advantages, a major concern that has resulted in limited marketed formulations is the physical instability of these complex formulations. Physical instability is often manifested as phase heterogeneity, where the drug and carrier migrate and generate distinct phases, which can be a prelude to recrystallization. One important factor that dictates the physical stability of ASDs is the spatial distribution of API in the polymeric matrix. It is generally agreed that intimate mixing of the drug and polymer is necessary to achieve maximum stabilization, and thus understanding the factors controlling phase mixing and nano-domain structure of ASDs is crucial to rational formulation design. The focus of this thesis work is to better understand the factors involved in phase mixing on the nanometric level and get insights on the role of excipients on overall stabilization of these systems. The central hypothesis of this research is that an intimately mixed ASD will have better physical stability as compared to a partially homogeneous or a non-homogeneous system. Our approach is to probe and correlate phase homogeneity and intermolecular drug-excipient interactions to better understand the physical stability of ASDs primarily using solid-state nuclear magnetic resonance (SSNMR) spectroscopy and other solid-state characterization tools. A detailed investigation was carried out to understand the role of hydrogen bonding on compositional homogeneity on different model systems. A comprehensive characterization of ternary ASDs in terms of molecular interactions and physical stability was studied. Finally, long-term physical stability studies were conducted in order to understand the impact of different grades of a cellulosic polymer on phase homogeneity for two sets of samples prepared via different methods. Overall, through this research an attempt has been made to address some relevant questions pertaining to nano-phase heterogeneity in ASDs and provide a molecular level understanding of these complex systems to enable rational formulation design.

The pharmaceutical industry is at a critical juncture. With little remnants of the “Golden Age of the Pharmaceuticals” and applied pressure from large companies experiencing a dissipation of proprietary compounds, trends indicate a transition from a decade of stagnant productivity to one in which high throughput screening technologies and computational chemistry have diversified the discovery of new chemical entities (NCE). Despite these advances, drug discovery has been challenged by chemical entities that present delivery limitations due to the properties of their molecular structure. A recent evaluation of development pipelines indicated that approximately 70% of drug candidates exhibit poor aqueous solubility; thereby, resulting in erratic dissolution and insufficient bioavailability. Due to intrinsic physical properties, these compounds are known by the biopharmaceutics classification system (BCS) as class II compounds and are amendable to solubility and bioavailability enhancement platforms. Approaches such as pH adjustment, micronization, nanosuspensions, co-solvent solubilization, cyclodextrin inclusion complexation, salt formation, emulsified drug formulations and amorphous solid dispersions (ASD) are commonly utilized to maximize bioavailability and enrich in vivo absorption by prolonging exposure to high concentrations of dissolved drug in the gastrointestinal tract (GIT). Single-phase amorphous systems, such as solid dispersions, have been the focal point of the aforementioned practices as a result of their ability to promote a state of drug supersaturation over an extended duration of time. Within the structure of this dissertation, the application of concentration enhancing polymers for bioavailability enhancement of low solubility compounds was evaluated using solvent and fusion-based solid dispersion technologies. Exploiting a variety of analytical methodologies and tools, formulations produced by spray drying and hot melt extrusion (HME) techniques were investigated for sufficient dissolution enhancement. Studies revealed the selected formulation approaches provided a viable platform for manufacturing solid dispersions by illustrating systems that offered rapid and prolonged periods of supersaturation. While of the applications of single-phase amorphous solid dispersions are continuously expanding, their dissolution behavior is not as well understood. The overarching objective of dissolution testing during formulation development is to achieve biological relevance and predict in vivo performance. Proper in vitro dissolution testing can convey the influence of key in vivo performance parameters and be implemented for assessment and comparison of ASD formulations. Studies suggest that existing research fails to accurately address the intricacies associated with the supersaturated state. Upon solvation and during transit in the GIT, several high-energy drug-containing species are present in addition to free drug. Although these species are not absorbed in vivo, they play a pivotal role in generating and maintaining the supersaturation of a drug substance and function to replenish the supply of free drug as it permeates across the gastrointestinal membrane. Established dissolution apparatuses and methodologies in the United States Pharmacopeia (USP) focus on evaluation of total dissolved drug and may not be physiologically relevant for determining the amount of drug absorbed in vivo. Within the framework of this dissertation, a dissolution methodology was designed to reflect the physiochemical, physiological and hydrodynamic conditions that transpire throughout dissolution and absorption of an ASD during transit in the GIT. The apparatus and model present the ability to understand the kinetics and mechanisms of dissolution, supersaturation and nucleation. To support this hypothesis, analytical methods including high pressure liquid chromatography (HPLC) with ultraviolet (UV) detection were developed and fully validated. In parallel, a novel plasma membrane treatment was established to fabricate biomimetic membranes that possessed a hydrophilic and hydrophobic surface. The treated membranes are comprised of applied surface chemistries that emulate the unstirred aqueous layer created by microvilli protruding from the intestinal epithelial membrane as well as lipophilic constituents corresponding to the epithelial lipid membrane. Calculated in vitro similarity (f2) and difference (f1) factors support the hypotheses that plasma treated microporous polymer membranes exhibit biorelevant properties and demonstrate adequate biorelevance for in vitro dissolution studies. The described dissolution methodology has been applied as a tool for selection of candidates to move forward to pharmacokinetic studies. In a culminating study, in vitro – in vivo correlations (IVIVC) were performed employing the universal membrane-permeation non-sink dissolution method for formulations of Carbamazepine. To demonstrate the utility of the methodology, multiple level C correlations were established. The membrane-permeation model enables quantitative assessment of drug dissolution and absorption and offers a means to predict the relative in vivo performance of amorphous solid dispersions for BCS class II drug substances. / Chemistry

Amorphous solid dispersion (ASD) is a popular method to increase drug solubility and consequently poor drug bioavailability. Cellulose ω-carboxyesters were designed and synthesized specifically for ASD preparations in Edgar lab that can meet the ASD expectations such as high Tg, recrystallization prevention and pH-triggered release due to the free -COOH groups. Rifampicin (Rif), Ritonavir (Rit), Efavirenz (Efa), Etravirine (Etra) and Quercetin (Que) cellulose ester ASDs were investigated in order to increase drug solubility, prevent release at low pH and controlled release of the drug at small intestine pH that can improve drug bioavailability, decrease needed drug content and medication price to make it affordable in third world countries, and extent pill efficiency period to improve patient quality of life and adherence to the treatment schedule. The studies were compared with cellulose based commercial polymers to prove the impact of the investigation and potential for the application. Furthermore, the in vitro results obtained were further supported by in vivo studies to prove the significant increase in bioavailability and show the extended release. The need of new cellulose derivatives for ASD applications extended the research area, the design and synthesis of a new class of polymers, alkyl cellulose ω-carboxyesters for ASD formulations investigated and the efficiency of the polymers were summarized to show that they have the anticipated properties. The polymers were synthesized by the reaction of commercial cellulose alkyl ethers with benzyl ester protected, monofunctional hydrocarbon chain acid chlorides, followed by removal of protecting group using palladium hydroxide catalyzed hydrogenolysis to form the alkyl cellulose wcarboxyalkanoate. Having been tested for ASD preparation, it was proven that the polymers were efficient in maintaining the drug in amorphous solid state, release the drug at neutral pH and prevent the recrystallization for hours, as predicted. / Ph. D.

Lors de cette dernière décennie, le développement de formes pharmaceutiques innovantes permettant d'améliorer l'efficacité, la sécurité et l'acceptabilité des médicaments pédiatriques est en pleine croissance. Les films orodispersibles (ODF) appartiennent à ces nouvelles formes galéniques améliorant la compliance des patients. Ils sont constitués d'une matrice de polymère hydrophile dans laquelle un ou des principe(s) actif(s) (PA) sont dissous ou dispersés. Après dépôt de l'ODF sur la langue ou dans la cavité buccale, la matrice se désagrège libérant le PA pour une action locale ou systémique. Dans cette étude, la mise au point d'ODF, par la méthode de coulée/évaporation de solvant a été explorée afin d'administrer un PA d'intérêt en pédiatrie, la tétrabénazine (TBZ). Les caractérisations physicochimiques et biopharmaceutiques des ODF ont mis en évidence une augmentation de la vitesse et du taux de dissolution de la TBZ induit par son état amorphe. Le système constitué d'un support polymère et d'un PA sous forme amorphe peut être assimilé aux dispersions solides amorphes (SD). Les études réalisées démontrent l'importance de la nature du polymère utilisé pour maintenir les propriétés initiales du système dans le temps. La formation de liaisons hydrogène entre la PA étudié et le polymère est un facteur essentiel pour assurer la stabilité des SD. De plus, l'incorporation de cyclodextrines (CD) prolonge l'état amorphe du PA en générant des liaisons hydrogène avec la TBZ et en l'entourant d'une barrière chimique. Cette association favorise la libération du PA par effet synergique améliorant la biodisponibilité. Cette forme innovante représente un intérêt majeur dans l'amélioration de l'observance dans le cadre d'un traitement pédiatrique / During the last decade, various strategies to develop innovating oral dosage forms for pediatric population were investigated in order to improve treatment efficiency, safety and acceptability. Among these new delivery systems, orodispersible films (ODF) present a great potential to enhance patient compliance. In ODF, drug is dissolved or dispersed in a hydrophilic film-forming polymer. Once the ODF is in the mouth, polymeric matrix disintegrates releasing the drug for local or systemic action. In this study, ODF, produced with the solvent casting/evaporation method, were developed to administer a drug of interest for pediatric population, the tetrabetazine (TBZ). Physicochemical and biopharmaceutic characterizations showed that ODF allowed a major improvement of TBZ dissolution profile in simulated saliva, mainly due to the amorphous state of the drug in ODF. ODF were identified as amorphous solid dispersion (SD) composed of both amorphous TBZ and polymer matrix. We demonstrated that the choice of the polymer plays an important role to maintain initial properties of the system and amorphous state stability over the time. H-bonding formation between TBZ and polymer is essential to assure the preservation of TBZ amorphous state. Moreover, the incorporation of cyclodextrins (CD), by generating H-bonding with TBZ, has extended its stability. By synergic effect, this association produces an improvement of drug release leading to promote bioavailability. As they are easy to swallow and allow enhancing treatment efficiency, ODF appear as suitable delivery forms for pediatric patients