| 摘要: | 當一種化合物的分子能夠以不同的排列方式組成結晶時，我們稱其為多型晶體。不同的多型晶體通常具有不同的物化性質，且在專利佈局上能延長藥品的生命週期，因此一直是製藥工程重要的課題之一。乙醯胺酚是一種常見的止痛藥，相較於市售的乙醯胺酚Form I結晶， Form II結晶的溶解度與可壓縮性更高，更有利於釋放與打錠，但Form II結晶的穩定度較差，很難穩定的製備。在本研究中我們開發了利用添加物控制多型晶體的結晶製程來製備乙醯胺酚Form II結晶，Form II結晶可以在分別添加五種添加劑，己二酸、富馬酸、蘋果酸、草酸或琥珀酸的情況下，透過乙醯胺酚的冷卻結晶製程來製備。我們探討了添加劑的用量、加入晶種和過飽和度S對乙醯胺酚形成多型晶體的影響，並發現：（1）添加入的添加劑越多，形成乙醯胺酚Form II晶體的可能性越高，（2）以富馬酸為晶種加入過飽和的乙醯胺酚水溶液可以誘導Form II晶體的成核，其他四種添加物則無此特性，（3）乙醯胺酚－草酸在水中的溶解度相圖顯示出乙醯胺酚－草酸可能會以複合物的形式存在於水溶液中，而這有可能是草酸造成乙醯胺酚選擇性地形成Form II晶體的原因之一，以及（4）在沒有添加劑的情況下，在S = 3.3到S = 3.6的範圍內進行冷卻再結晶可使Form II乙醯胺酚單獨成核，但在加入乙醯胺酚重量的百分之五十的富馬酸後，S的範圍可以拓展到 S = 1.5 到 5.7。通過配置濃度為58.82毫克乙醯胺酚、29.4毫克富馬酸/毫升的水溶液，並從攝氏75度以每分鐘一度的冷卻速率從 75度下降到10度，可以獲得約 1.47 克的乙醯胺酚Form II晶體（即產率 = 73.55%）。
我們也使用附有攪拌設備的結晶槽與管狀結晶槽進行乙醯胺酚的批示及連續式結晶，在批式結晶實驗中，乙醯胺酚Form II可以在有富馬酸的環境中結晶，但在經過長時間攪拌後乙醯胺酚Form II晶體都會轉變為較穩定的Form I。另一方面，乙醯胺酚Form II晶體可在特定的濃度以及流量下，藉由連續式結晶製程獲得，提高乙醯胺酚－富馬酸水溶液的流速與富馬酸的比例可以更穩定的獲得Form II的乙醯胺酚，適度降低乙醯胺酚的初始濃度也有助於緩解結晶沉澱於結晶管內的問題，並進而提升產率。
此外，我們也發現了乙醯胺酚溶液在加入馬來酸後由無色轉變為黃色，而顏色的改變與乙醯胺酚－馬來酸的共晶有關，本研究也同時報導了乙醯胺酚－馬來酸共晶的紅外光譜、光致發光光譜、溶解度相圖和三角相圖。
;Polymorphism is one of the important topics in pharmaceutical industry due to its ability in modulating the physicochemical properties and extending the life cycle of a drug substance. Form II paracetamol (PCA) is a popular drug substance attracting the interest of researchers due to its improvement for compressibility of PCA. However, its low stability has made it difficult to be produced in a large scale with a good reproducibility. In the present study, multicomponent crystallization was developed to prepare the metastable Form II PCA. Form II PCA crystals could be yielded by cooling crystallization in the presence of five additives: adipic acid (ADI), fumaric acid (FUM), DL-malic acid (MLC), oxalic acid (OXA) and succinic acid (SUC). The effects of the amounts of additives, seeding, and the degree of supersaturation, S, of PCA, on the polymorphic formation of PCA were thoroughly investigated. It was found that: (1) the more additives were added, the higher probability of forming Form II PCA crystals, (2) Form II PCA crystals could be induced by seeding the PCA aqueous solution with FUM, while the other four additives had failed to do so, (3) a new solution complex of PCA-OXA, evidenced by a concave upward curve in the solubility diagram, might be responsible for the selective nucleation of Form II PCA in the PCA-OXA aqueous solution, and (4) the range of S for nucleating Form II PCA was modulated from S = 3.3 to 3.6 in the absence of additive, and extended to 1.5 to 5.7 in the presence of 50 wt% of FUM. About 1.47 g of Form II PCA crystals (i.e. yield = 73.55 %) could be obtained by cooling crystallization from 75o to 10oC with 50 wt% of FUM with a concentration of 58.82 mg/mL and a cooling rate of 1oC/min.
Multicomponent crystallization was applied in a stirred tank for batch crystallization, and in a tubular crystallizer for continuous crystallization. In the experiments of batch crystallization, Form II PCA crystals could be nucleated by cooling crystallization with the assistance of FUM, and then the Form II PCA crystals were transformed to stable Form I PCA crystals after a long time upon agitation. On the other hand, the Form II PCA crystals were isolated by continuous crystallization with a concentration of 44 mg of PCA/mL of water with 50wt% of FUM and a flow rate of 150 mL/min.
In addition, the color of PCA aqueous solution had changed to yellow upon the addition of MAL, but the yellow color was not seen for the aqueous solution of each individual component. The IR spectrum, photoluminescence spectrum, solubility diagram, and phase diagram of PCA-MAL co-crystals were established. |
