罌粟鹼是一種昂貴的藥物，可從鴉片或複雜的化學合成獲得，它與大部分的藥物一樣具有低溶解度的缺點，因此將罌粟鹼游離鹼轉化成罌粟鹼鹽酸鹽是製藥工業中常用以提升其溶解度的策略之一，罌粟鹼鹽酸鹽的生產通常會使用到大量的有機溶劑，且難以透過冷卻再結晶或反溶劑添加再結晶來製備。為了克服這個問題，在本研究中我們利用反應漿料結晶法製備罌粟鹼鹽酸鹽。自甲醇中再結晶的罌粟鹼鹽酸鹽的熔點為213℃，與購買的罌粟鹼鹽酸鹽的熔點224℃相比下降了11℃。 粉末X光繞射儀則顯示出其可能具有多晶型。除了反應漿料結晶法，我們還透過其他常規方法（即溶液結晶和無溶劑機械化學）製備鹽酸罌粟鹼，在反應漿料結晶法中， 0.12克的罌粟鹼先與0.5毫升異丙醇溶液混合形成漿料，再與0.12毫升、濃度為3M的鹽酸水溶液（罌粟鹼與鹽酸的摩爾比為1:1）在25℃下反應8小時，產率87.52 wt％（0.116克），並用傅立葉轉換紅外線光譜、粉末X光繞射儀和示差掃描量熱儀鑑定產物。為了控制罌粟鹼鹽酸鹽的粒徑分佈，在罌粟鹼與鹽酸的反應20分鐘後，進行溫度循環，並成功地控制了罌粟鹼鹽酸鹽的粒徑分佈，罌粟鹼鹽酸鹽的晶體尺寸分布從115微米到177微米，最終增加到420微米到470微米，晶貌則從粒狀顆粒變為棱柱形狀，透過示差掃描量熱儀證明在溫度循環後罌粟鹼全部轉化為罌粟鹼鹽酸鹽。最後，藉由將15毫升含有0.3克罌粟鹼鹽酸鹽的飽和水溶液與0.798毫升、濃度1M的氫氧化鈉水溶液（罌粟鹼鹽酸鹽與NaOH的摩爾比為1：1）在25℃下反應1小時，可以回收罌粟鹼，產率則為92.06wt％（0.25克），回收的罌粟鹼的結晶為針狀晶體。;Most of the drugs discovered, such as papaverine are poorly water soluble. Papaverine is an expensive drug, obtained from opium or complicated synthesis. Converting the free base into papaverine hydrochloride salt was one of the strategies used in pharmaceutical industry to increase the solubility of papaverine. Production of papaverine hydrochloride usually involved the use of a large amount of organic solvent. In addition, papaverine hydrochloride was difficult to recrystallize either by cooling or antisolvent addition. To overcome this problem, reaction slurry crystallization was chosen in this study to produce papaverine hydrochloride. The melting point of papaverine HCl salt recrystallized from methanol was 213oC, off by 11oC compared with the melting point of the purchased papaverine HCl salt at 225oC. The PXRD pattern indicated the possibility of polymorphism. Papaverine hydrochloride was also prepared by other conventional methods (i.e. solution crystallization and solventless mechanochemistry) with the goal of comparing with the one prepared through the intensified method (i.e. reaction slurry crystallization). Papaverine hydrochloride was synthesized through reaction slurry crystallization by reacting a slurry containing 0.12 g of papaverine and 0.5 mL of isopropyl alcohol slurry with 0.12 mL of 3M HCl having a molar ratio of papaverine to HCl of 1 to 1 at 25oC for 8 h. The solids were characterized by FT-IR, PXRD and DSC with a yield of 87.52 wt% (0.116 g). To control the particle size distribution of papaverine hydrochloride salt, after a 20 min reaction time for reaction slurry crystallization of papaverine HCl, temperature cycling was performed. The particle size distribution was successfully controlled. The crystal sizes of papaverine HCl increased from 115 to 177 μm to finally 420 to 470 μm. Crystals habits changed from grainy particles to finally prismatic shape. The conversion of papaverine free base to papaverine hydrochloride salt was eventually completed after temperature cycling as verified by DSC. Papaverine could be recovered by reacting 15 mL of water saturated with 0.3 g of papaverine hydrochloride with 0.798 mL of 1M NaOH having a molar ratio of papaverine hydrochloride to NaOH of 1 to 1 at 25oC for 1 h. The result was characterized by FT-IR, PXRD and DSC with a yield of 92.06 wt% (0.25 g). The crystal habits of recovered papaverine free base exhibited a needle crystal habit.
