Browsing by Subject "Amorphous solid dispersions"
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Item Amphiphilic polymers: crystallization-assisted Self-assembly and applications in pharmaceutical formulation(2013-04) Yin, LigengAmphiphilic polymers are macromolecules that simultaneously contain hydrophobic and hydrophilic components. These molecules not only attract much attention in academic research but also are important materials in industry. Application areas include detergency, oil field, paints, agriculture, food, cosmetics, and pharmaceutics. This dissertation highlights my efforts since the November of 2007 on three separate systems of amphiphilic polymers, which addresses both the fundamental self-assembly behavior in solution and applications in pharmaceutical formulation. Chapter 2 describes the self-assembled micelles in water that contain semicrystalline polyethylene (PE) as the core-forming material. Poly(N,N-dimethylacrylamide)-polyethylene (AE) diblock copolymers were chosen as the model system. An AE diblock copolymer with relatively low PE composition resulted in micelles with oblate ellipsoidal cores in water, in which crystalline PE existed as flat disks at the center and rubbery PE resided on both sides. In contrast, a control sample with a rubbery polyolefin as the hydrophobic component resulted in micelles with spherical cores in water. The morphology transition was ascribed to the crystallization of PE. The heat-assisted direct dissolution for sample preparation was identified as a stepwise "micellization-crystallization" procedure. In addition, the morphology of the aggregates exhibited much dependence on the composition of AE copolymers, and wormlike micelles and bilayered vesicles were obtained from samples with relatively high PE compositions. Chapter 3 demonstrates the precise synthesis of glucose-containing diblock terpolymers from a combination of anionic and reversible addition-fragmentation chain-transfer (RAFT) polymerizations. The resulting micelles exhibited excellent stability in several biologically-relevant media under in vitro conditions, including 100% fetal bovine serum. These particles may find applications as serum-stable nanocarriers of hydrophobic drugs for intravenous administration. Chapter 4 presents the development of novel cellulose derivatives as matrices in amorphous solid dispersions for improving the bioavailability of poorly water-soluble drugs in oral administration. Hydroxypropyl methylcellulose (HPMC) was modified with monosubstituted succinic anhydrides using facile anhydride chemistry, and the resulting materials simultaneously contained hydrophobic, hydrophilic, and pH-responsive moieties. Several HPMC esters of substituted succinates exhibited more effective crystallization inhibition of phenytoin under in vitro conditions than a commercial hydroxypropyl methylcellulose acetate succinate (HPMCAS). (341 words)Item Effects of additives on the molecular-level behavior of disordered pharamceuticals(2020-12) Amponsah-Efah, KwekuAmorphous solid dispersions (ASDs) can improve the oral bioavailability of poorly water-soluble drugs. However, the physical instability of the amorphous form, denoted by the propensity to recrystallize, is a major barrier to the use of ASDs. The overarching goal of this thesis was to understand the mechanisms by which two major classes of additives – antiplasticizers (various polymers) and plasticizers (mainly glycerol) – affect the physical stability of amorphous formulations, in the dry solid form, as well as in aqueous solution. In the first project, we investigated the impact of the strength of drug–polymer interactions, on the dissolution performance of ASDs. With ketoconazole and three polymers as model compounds, we observed that the interactions that stabilize amorphous drugs in the solid state, can also be relevant and important in sustaining the level of supersaturation in aqueous solution. The second project explored the use of analytical ultracentrifugation as a novel technique for characterizing drug–polymer interactions in aqueous buffers. It was possible to quantify the “free” versus “bound” fractions of drug in aqueous solution, and to semi-quantitatively assess the impact of interactions on the dissolution performance of ASDs. The third and fourth projects evaluated the effects of glycerol on the molecular mobility and physical stability of amorphous itraconazole (ITZ), in the “solid” state. It is well-known that small molecule plasticizers, such as water or glycerol, increase the molecular mobility and accelerate the crystallization of amorphous drugs. In the case of amorphized ITZ, however, glycerol at low concentrations did not cause physical instability. Rather, the smectic state (one of the intermediate liquid-crystalline phases of ITZ) was selectively stabilized. The mechanism by which glycerol stabilized the smectic state was investigated with high resolution techniques (synchrotron diffractometry, differential and adiabatic scanning calorimetry, and spectroscopy). The results revealed that additives with fast dynamics, can drive weak first-order (or second-order) intermediate liquid-crystalline phase transitions, to strong first-order transitions, by a possible coupling of the additive concentration to the order parameter. We also demonstrated that the stabilized smectic state can perform the dual role of maintaining good physical stability while achieving adequate dissolution performance.