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Ideal freeze drying injection should be satiation, spotlessly white, fine and smooth, porous solid. In actual large scale production, as complex process technology parameters, flexible operation of freeze drying machine, so the result appearance of injection is often dissatisfactory, many bad situations will happen, such as injection foaming, injection stratified, surface crack, color difference, etc. Because of these, great economic losses happened.
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TOPTION as professional vacuum freeze dryer manufacture in China, we have strong specialist team to develop freeze drying technology, in order to help our customers avoid the above bad situations, TOPTION engineers analysis reasons and provide related solutions based on more than 10 years technical experience, hope could help you avoid economic losses:
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1. Color difference – drug after freeze drying, one bottle drug or a batch of drug, exist color inconsistent phenomenon.
The reasons of color difference and related solutions:
1) Drug itself color or the color caused after freeze dried, these two reasons both maybe cause final color difference. If you discover color difference at the middle part of medicine, you could aviod it by adjust freeze drying curve, together with aeration, open your products water channel, through this method, color difference of freeze dried products will be improved greatly.
2) Some drugs color will change with temperature reduce during freeze drying process, this is a physical phenomenon, products’ pre-freezing temperature is more lower, the color difference will happen more easier. You could use accurate method to measure products’ eutectic point temperature, but as many freeze dried products is amorphous form (such as add a percentage buffer salt/ saccharose etc disaccharides), these kind products after solidification starting, also need keep reduce temperature then products will continous solidify, so for this kind products, please use the temperature when sample totally freezed (collapse temperature), generally, set pre-freezing temperature should be lower 5~10℃ than collapse temperature.
3) High moisture in products or uneven distribution of moisture in the products. You could use slow freeze and products temperature please not reduce more, lower 10℃ than eutectic point is better. Suggest use uniform heating sublimation method, and also could adjust prescription, incease skeleton stabilizer dosage.
4) Fusion happened during vacuum freeze drying process. You could adjust freeze drying curve, increase heat supplied, make the moisture finish drying in a sublimation stage, please pay attention to control the vacuum degree and the level that cold trap could reach. Or you also could lengthen drying time base on the original drying curve, so as to reduce products’ moisture. Of course, prescription contains relatively high proportion of inorganic salt and gelatin,etc,significantly reduced the eutectic point and a sublimation temperature is too high, lead to products fusion.
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2. Injection stratified – top and bottom inhomogeneity, top loose and bottom tight, top part is loose and almost no water, buttom part is tightness and water content is larger.
The reasons of injection stratified and related solutions:
1) The solubility of drug is small, after filling drug solution in bottle and placing long time, or as drug liquid separate out when temperature dropping, then precipitate appear. You could increase freeze drying speed or decrease solute content to reach your purpose.
2) Use steps sublimation method, sublimation temperature（aeration or aeration method) is not approproate, temperature jump is too large, specially in the first step large water contents have not be removed. Solutions: in first sublimation temp, we set one time drying temperature and time. One time drying temperature is related with time, this method purpose is receiving more than 95% water sublimation.
3) Compressor and vacuum pump performance is weaken during freeze drying process, such as vacuum degree could not drop well, cold trap temperature is not low enough (generally cold trap temperature ＜-65℃). Please find the vacuum freeze dryer reason and repair in time.
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3. Atrophy – drug and bottle seperate, drug has shrink.
The reasons of atrophy and related solutions:
1) Atrophy contains out of the box atrophy and place atrophy, the first one caused by many reasons, contains all stratified situations.
2) If is place atrophy, maybe as high moisture content, please control products’ moisture content, so as to decrease moisture content.
3) If products redissolve or the ratio of clinical don’t has problems, maybe as this products belongs to difficult freeze drying products, suggest could produce some sample to cheak until have produce qualified products, then keep improving.
4) If products redissolve or the ratio of clinical has problems, please find reasons from prescription, if prescription is same with orginal research, then must adjust freeze drying curve.
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4. Injection gush bottle – because the pre-freezing temperature have not reach lower than products’ eutectic point, freeze loose. Or as heating too rapid when sublimation drying, local overheating, some part products melt to liquid, under high vacuum degree condition, small capacity liquid gush from the crack of drying solid surface.
The reasons of gush bottle and related solutions:
1) Products’ eutectic point is low, such as lactose is amorphous filler, its eutectic point temperature is -32℃; 10% glucose -27℃, trehalose is amorphous filler, its eutectic point temperature is -32℃,etc. Freeze drying maybe couldn’t freeze totally, specially in summer season or when vacuum freeze dryer performance is poor ( such as compressor is not well or compressor cooling water temperature is over high), according to common freeze drying curve, such as conduction oil reach -40℃, temperature protect 3hours, will cause products not freeze totally.
2) Solutions: Strictly control pre-freezing temperature, such as disaccharides (eutectic point temperature is lower than -30℃, choose pre-freezing temperature should at -45℃, products’ temperature should lower than -40℃, products’ temperature better could reach -45℃).
3) If freeze dried products contains a buffer and high solid content, pre-freezing temperature also need to low enough, common choose standard is product’s temp. lower 10℃ than eutectic point temp, and need keep in a period time, after freezing totally, then begain sublimation operation.
4) Control the first sublimation temperature, please choose uniform heating method, and before products’ water line have not reach the bottom, not set too high conduction oil temperature is better ( generally conduction oil temp should be lower than 0℃). For these kinds of products, you could adopt repeatedly coolling sublimation method to solve problems.
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More questions welcome send us comments, or you need some technical support, welcome contact our specialist
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