Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent, ME4 4TB, Kent, UK.
Pharm Res. 2012 Aug;29(8):2139-56. doi: 10.1007/s11095-012-0743-3. Epub 2012 Apr 5.
To co-crystallise mannitol and lactose with a view to obtaining crystals with more favourable morphological features than either lactose or mannitol alone, suitable for use as carriers in formulations for dry powder inhalers (DPIs) using simultaneous engineering of lactose-mannitol mixtures.
Mannitol and lactose individually and the two sugars with three different ratios were crystallised/co-crystallised using anti-solvent precipitation technique. Obtained crystals were sieved to separate 63-90 μm size fractions and then characterised by size, shape, density and in vitro aerosolisation performance. Solid state of crystallized samples was studied using FT-IR, XRPD and DSC.
At unequal ratios of mannitol to lactose, the elongated shape dominated in the crystallisation process. However, lactose exerted an opposite effect to that of mannitol by reducing elongation ratio and increasing the crystals' width and thickness. Crystallised β-lactose showed different anomers compared to commercial lactose (α-lactose monohydrate). Crystallised α-mannitol showed different polymorphic form compared to commercial mannitol (β-mannitol). Crystallised mannitol:lactose showed up to 5 transitions corresponding to α-mannitol, α-lactose monohydrate, β-lactose, 5α-/3β-lactose and 4α-/1β-lactose. In vitro deposition assessments showed that crystallised carriers produced more efficient delivery of salbutamol sulphate compared to formulations containing commercial grade carriers.
The simultaneous crystallization of lactose-mannitol can be used as a new approach to improve the performance of DPI formulations.
通过共结晶甘露醇和乳糖，获得具有比单独的乳糖或甘露醇更有利的形态特征的晶体，适合用作干粉吸入剂（DPI）制剂中载体，同时对乳糖-甘露醇混合物进行工程设计。
分别使用抗溶剂沉淀技术对甘露醇和乳糖以及两种糖以三种不同比例进行结晶/共结晶。获得的晶体进行筛分，分离出 63-90μm 的粒径范围，然后通过粒径、形状、密度和体外雾化性能进行特征描述。使用傅里叶变换红外光谱（FT-IR）、X 射线粉末衍射（XRPD）和差示扫描量热法（DSC）研究结晶样品的固态。
在甘露醇与乳糖比例不等的情况下，在结晶过程中，长形占主导地位。然而，乳糖通过降低伸长率并增加晶体的宽度和厚度对甘露醇产生相反的影响。结晶的β-乳糖与商业乳糖（α-乳糖一水合物）相比，显示出不同的差向异构体。结晶的α-甘露醇与商业甘露醇（β-甘露醇）相比，显示出不同的多晶型形式。结晶的甘露醇：乳糖显示出多达 5 个对应于α-甘露醇、α-乳糖一水合物、β-乳糖、5α-/3β-乳糖和 4α-/1β-乳糖的转变。体外沉积评估表明，与含有商业级载体的制剂相比，结晶载体可更有效地输送硫酸沙丁胺醇。
乳糖-甘露醇的同时结晶可作为改善 DPI 制剂性能的新方法。
