Spray-dried lactose was used as a direct compression excipient in the production of tablets as far back as the 1960s. Until today, this type of product is still the most commonly used excipient in the direct compression process. As there are many companies that currently produce spray-dried lactose, and there are many different types and specifications of spray-dried lactose products on the market, the factors that affect the compressibility of spray-dried lactose are complicated. Therefore, it is necessary for drug manufacturers to understand each of them. The nature of spray-dried lactose products and the new trend of spray-dried lactose products, so that in the application of the appropriate types and specifications to improve the quality of tablets.
Small particle size lactose can increase tablet strength. Spray drying lactose is a product obtained by screening the product obtained by spray-drying a saturated suspension of α-lactose monohydrate crystals, resulting in a narrow particle size distribution and good flowability. It mainly consists of a crystalline and saturated amorphous skeleton of alpha-lactose monohydrate (15% to 20%). In a saturated solution, lactose exists as two optical isomers, alpha and beta, with [alpha]-lactose accounting for 40% and [beta]-lactose accounting for 60%. This ratio does not change during spray drying, especially at higher temperatures. In spray-dried lactose, β-lactose is mainly present in the amorphous matrix, and its proportion in spray-dried lactose is 9% to 12%.
Spray-dried lactose with different particle sizes has a relatively obvious difference in compressibility. Crystallization of α-lactose monohydrate can satisfy the flowability requirements of direct compression, but it is a brittle substance. Although studies have shown that the probability of causing splinters is very low, when the particle size is reduced to 45 μm or Even smaller, it changes from brittle to plastic. Therefore, α-lactose monohydrates of different particle sizes exhibit different compressibility. The compressibility of spray-dried lactose is also related to the initial particle size of α-lactose monohydrate. The initial particle size is determined by first ultrasonically dispersing spray-dried lactose in a saturated solution of isopropyl alcohol to form a suspension. Laser diffraction and other methods to determine the particle size.
At the same pressure, tablets made from small-sized lactose have higher strength. A recent study compared the compressibility of 15 spray dried lactoses of 15 different particle sizes and different amorphous composition. In this experiment, a tableting pressure of 10 kg was used, a 13 mm circular die, and a tablet weight of 500 mg. The results show that, under the condition that the amorphous composition is the same, reducing the particle size can increase the hardness of the tablet. The latest generation of spray-dried lactose takes advantage of this. The study showed that two commercial products with an average particle size of 34 μm and 20 μm, respectively (both products contained 17% of amorphous ingredients, were moisture-balanced at 30% relative humidity before tableting and were added. 0.5% magnesium stearate as a lubricant), at the same pressure, the small particle size of lactose can increase the hardness of the tablet by 30% to 50%, which is of great significance for the prescription of poor compressibility.
The moisture must be strictly controlled during production. The compressibility of many excipients is affected by the moisture content. For example, increasing the moisture content of microcrystalline cellulose can increase its compressibility. In spray-dried lactose, the effect of moisture content on compressibility is greater and more complex than that of microcrystalline cellulose. For example, the formula composition is 99.5% spray-dried lactose and 0.5% magnesium stearate under different moisture conditions, and the result of tableting with 10-20 kg force is: When the moisture content increases from 0.1 to 0.3, the tablet The hardness of the agent continues to increase; however, when the moisture increases to 0.6, the tablet hardness decreases dramatically. The reason is that the moisture in the air is mainly absorbed by the amorphous part of the spray-dried lactose. Although the lubricating effect of moisture can increase the initial hardness of the tablet, moisture can also affect the glass transition temperature of the amorphous portion of the lactose. When the moisture reaches a critical value, the glass transition temperature is lower than room temperature. In this case, the amorphous portion will change from a glassy state to a stable state. At this time, the amorphous state will produce metaspin and become α-lactose monohydrate crystal. . At room temperature, this conversion occurs when the water reaches 0.4 to 0.5. This crystallisation will have two effects: the proportion of beta-lactose in the spray-dried lactose is reduced; the compressibility of the entire excipient is reduced. Under normal circumstances, spray-dried lactose water should be controlled at 0.15 during production. In addition, in order to keep the spray-dried lactose for a period of two years, closed packaging should be used to reduce water absorption.
The development prospect of stable lactose is promising In order to avoid the recrystallization process of amorphous lactose, some companies solve this problem by changing the packaging materials. In addition, since the formation of α-lactose monohydrate crystals is a rather slow crystal transformation process, researchers hope to develop a suitable rapid crystallization method for the preparation of more stable spray-dried lactose products.
Recent studies have found that under certain temperature and humidity conditions, amorphous lactose crystallizes rapidly. The result is not a-lactose monohydrate but a stable mixed form of α/β. In this crystalline form, the β-lactose content is consistent with that in the amorphous framework. Therefore, the spray-dried lactose produced under this condition, its original α-lactose monohydrate crystals are contained in a stable crystalline framework instead of an amorphous skeleton, and this spray-dried lactose is more stable.
Studies have shown that at 20°C, the traditional spray-dried lactose has a rapid increase in water content at 20% to 50% relative humidity, and when the crystallization point is reached, the water content decreases; whereas, the stable spray-dried lactose has a humidity of 20%. At 90% relative humidity, there is only a slight increase in moisture. Therefore, stable spray-dried lactose has a better prospect in the development of direct compression excipients.

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