Collaborative Research: How do biopolymers dissolve? Identification of rate-limiting steps as a framework to design polymers with tailored dissolution.

聚合物是一种长链分子，广泛应用于从油漆到冰淇淋的各种产品中。自然界提供了大量的生物聚合物，如纤维素和淀粉，它们通常是良性的，可以在环境中降解为水和二氧化碳。它们可以被化学改性以产生例如广泛有用的纤维素衍生物，其被社会广泛使用，包括在药物中。通过吞咽药片使药物进入体内变得越来越困难，因为很少有现代药物容易溶于水。重要的是，药物可以在消化系统的正确区域从片剂中溶解，以便它可以被吸收并对身体发挥其治疗作用。生物聚合物可用于帮助改善药物溶解度和释放。然而，由于新一代药物越来越难以吸收，因此重要的是要更多地了解聚合物如何溶解和释放其货物，以及如何对这些聚合物进行化学改性，使其更有效地输送药物和其他难溶性添加剂。这项研究调查了聚合物如何与水相互作用，以及这反过来如何影响聚合物的溶解速率。聚合物将与憎水添加剂（许多药物可以被描述为憎水）混合，揭示这如何改变溶解。最后，将设计新的生物聚合物衍生物，即使在存在憎水添加剂的情况下，也能与水保持良好的相互作用。目标是开发比现有聚合物更有效的聚合物，以释放水溶性差的药物（和其他添加剂）。这项工作的广泛影响包括培训研究生和本科生，包括代表性不足的少数民族和妇女，包括为研究生制定专业技能计划。 技术摘要聚合物溶解既具有根本性又具有实用性。它与小分子溶出度显著不同，并且通常存在问题。关键问题包括缓慢或控制不良的溶解和不期望的凝胶化。还含有小分子添加剂的系统是常见的，例如用于增强疏水性添加剂的水溶性的无定形固体分散体（ASD）。在这些系统中，添加剂和聚合物溶解速率的不匹配可导致系统故障（例如添加剂沉淀）。缺乏对添加剂如何影响聚合物溶解的基本理解。在此，我们建议阐明添加剂对生物聚合物溶解的速率限制步骤的影响，特别是对于多糖（PS）衍生物，其良性性质和潜在的改性使它们非常适合于具有技术重要性的聚合物/添加剂系统。一组新的PS衍生物将被设计和合成，以测试关键假设的水化程度的重要性，以及特定的功能基团后的溶解速率的影响。选择性PS氧化和卤化将允许用ω-氨基和ω-巯基羧酸取代。将在存在和不存在模型添加剂的情况下测量PS溶出速率;电离、反离子尺寸/性质和空间位阻的影响测试将揭示水合速率/程度是否是关键速率限制步骤。通过阐明释放所需的聚合物结构特征，目标是开发用于水溶性差的化合物的新的口服递送系统。学生将合作阐明聚合物溶解的限速步骤，合成和表征聚合物，测试有和没有精心选择的添加剂的溶解速率，并将产生的基本理解应用于完善理论和增强聚合物设计。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估而被认为值得支持。

Non-technical abstractPolymers are very long chains of molecules and are widely used in products ranging from paint to ice-cream. Nature provides an abundance of biopolymers such as cellulose and starch which are typically benign and can degrade to water and carbon dioxide in the environment. They can be chemically modified to produce, for example, broadly useful cellulose derivatives that are widely employed by society, including in medicines. Getting a medicine into the body by swallowing a tablet is becoming increasingly difficult because few modern drugs easily dissolve in water. It is important that a drug can be dissolved from a tablet in the right region of the digestive system so that it can be absorbed and exert its therapeutic effects on the body. Biopolymers can be used to help improve drug solubility and release. However, because new generations of drugs are increasingly difficult to absorb, it is important to understand more about how polymers dissolve and release their cargo, and how to chemically modify these polymers to make them even more effective at delivering drugs and other poorly soluble additives. This research investigates how polymers interact with water, and how this in turn impacts the rate of polymer dissolution. Polymers will be mixed with water-hating additives (many drugs can be described as water-hating), revealing how this changes dissolution. Finally, new biopolymer derivatives will be designed that maintain a good interaction with water, even in the presence of water-hating additives. The goal is to develop polymers that are more effective than existing polymers at releasing poorly water-soluble drugs (and other additives). Broad impacts of this work include training graduate and undergraduate students including under-represented minorities and women, including developing a professional skills program for graduate students. Technical abstractPolymer dissolution is both fundamentally and practically important. It differs significantly from small molecule dissolution and is often problematic. Key issues include slow or poorly controlled dissolution, and undesired gelation. Systems that also contain small molecule additives are common, for example amorphous solid dispersions (ASDs) for enhancement of aqueous solubility of hydrophobic additives. In these systems, mismatch of additive and polymer dissolution rates can lead to system failure (e.g. additive precipitation). Fundamental understanding of how additives impact polymer dissolution is lacking. Herein, we propose to elucidate the impact of additives on the rate limiting steps of biopolymer dissolution, in particular for polysaccharide (PS) derivatives, whose benign nature and potential for modification make them well suited for polymer/additive systems of technical importance. A set of novel PS derivatives will be designed and synthesized to test key hypotheses about the importance of hydration extent, as well as the impacts of specific functional groups upon dissolution rate. Selective PS oxidation and halogenation will permit substitution with omega-amino and omega-mercaptocarboxylic acids. PS dissolution rates will be measured in the presence and absence of model additives; tests of impact of ionization, counterion size/nature, and steric hindrance will reveal whether hydration rate/extent is the key rate limiting step. By elucidating polymer structural features necessary for release, the goal is to develop new oral delivery systems for poorly water-soluble compounds. Students will collaborate to elucidate rate-limiting steps in polymer dissolution, synthesize and characterize polymers, test dissolution rates with and without carefully selected additives, and apply the generated fundamental understanding to refine theory and enhance polymer design.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.