The stability study of preparationsis to investigate the law of the quality characteristics of preparations over time under the influence of various environmental factors (such as temperature, humidity, light exposure, etc.), and based on this, it is the prescription, process, packaging, and storage conditions of the drug. Provide supporting information for the determination of transportation and expiry date. Passing the compatibility of raw materials and influencing factors in the early stage of formulation process development can provide the necessary basis for the formulation of formulations, processes, and packaging materials. However, some factors that affect the quality characteristics of formulations require long-term stability investigations. It can be found that, for example, the dissolution rate, in the development process of the formulation, the dissolution rate of the solid formulation is often reduced during the accelerated and long-term test process. The following editor will talk to you about the reasons for the slow dissolution of solid tablets and capsules in the accelerated and long-term tests. The drug content and impurities have not changed.
For polymorphic drugs, under different temperature and humidity, the crystal form may be transformed. Studies have shown that temperature has a greater influence on the crystal form transformation of the drug, and humidity affects the process of pseudopolymorphic transformation. If the bulk drug is a polymorphic drug, when the dissolution slows down during the accelerated test, you can investigate whether the drug has crystallized during the accelerated test. Commonly used methods for detecting crystal transformation include X-ray diffraction; polarized light microscope technology; differential scanning calorimetry; infrared spectroscopy; Raman spectroscopy; solid-state nuclear magnetic technology. If the interference of excipients is relatively large, the proportion of raw materials in the prescription can be increased, and the crystal form test can be carried out after the preparation is produced according to the production process of the preparation.
For APIs that become sticky when exposed to water, under accelerated test conditions, the ingredients in the formulation may aggregate after the formulation absorbs moisture, causing the particles to become larger and slower to dissolve after the tablet disintegrates. In addition, when the proportion of the main drug is relatively large, under the accelerated and long-term test conditions, the drug substance may also undergo microscopic migration and aggregation, which will increase the particle size of the drug substance and slow down the dissolution.
1) When a low-substituted hypromellose is used as a disintegrant in a tablet, if the preparation contains an alkaline substance, the disintegration time of the tablet will be prolonged after long-term storage.
2) Cross-linked povidone has strong adsorptivity, especially for APIs containing carboxyl and phenolic hydroxyl groups. When the active ingredient in the formulation is relatively small, the solid formulation may be caused by its adsorption during long-term storage. Dissolution slows down.
3) Sodium carboxymethyl starch disintegrates mainly by absorbing water and swelling, and it is hygroscopic. However, the disintegration effect cannot be reduced after moisture absorption. Therefore, in the stability test, the sodium carboxymethyl starch may absorb moisture. It will lead to prolonged disintegration time of the tablet and slower dissolution.
4) When croscarmellose sodium is used as a disintegrant, if there are hygroscopic water-soluble materials in the formulation, it may also cause the dissolution rate of the tablet to decrease. The possible reason is that the water-soluble materials in the prescription (such as lactose) partially dissolve after absorbing moisture and form voids, and the disintegrant swells by absorbing water. However, it has a small expansion ratio after absorbing water, and only fills the voids created by the dissolution of lactose. The disintegration force of the tablet is small, the disintegration is slower, and the dissolution time is prolonged.
1) The biggest disadvantage of povidone (PVP) as a binder is its strong hygroscopicity. After PVP absorbs moisture, the Tg (glass transition temperature) changes, that is, it changes from the glass state to the rubber state, which makes the particles in the formulation form hard blocks. Prevent the dissolution of the drug. If the prescription contains ingredients such as stearic acid, formaldehyde, peroxide, etc., it can also interact with PVP under accelerated conditions to reduce the space between particles, prevent the dissolution medium from entering the tablet, and slow down the dissolution.
2) Sodium carboxymethyl cellulose is also a hygroscopic binder, which can absorb a large amount of water (>50%) under high humidity conditions. In a tablet, this property can make the disintegration time of the tablet slower. Prolonged, may affect the speed of the drug.
Magnesium stearate is a commonly used lubricant. Because of its strong hydrophobicity, when the amount of magnesium stearate is large, after long-term storage, the hydrophobic magnesium stearate will be adsorbed on the surface of the drug substance particles or preparations to make the drug particles or The wetting time of the tablet is prolonged, hindering the dissolution of the drug. In addition, in general, differential silica gel has a good flow aid, strong hydrophilicity and polarity, and is helpful for the dissolution of drugs. However, in the actual development process, the use of micro-powder silica gel may lead to reduced drug dissolution under accelerated conditions. slow. The editor speculates that it may be the reason for choosing hydrophobic micro-powder silica gel.
It is reported in the literature that cellulose derivative excipients are prone to gelation at higher temperatures to form a gel, thereby slowing down the dissolution of the drug.
1) Preparations containing gelatin in the prescription often experience a decrease in the dissolution rate during long-term storage. The main reason is the cross-linking effect of gelatin. Cross-linking can make gelatin become a swollen, thin, tough and elastic water-soluble film, which prevents the dissolution of the drug. Studies have found that both high temperature and high humidity are beneficial to the cross-linking of gelatin. If there are formaldehyde, glutaraldehyde, glyoxal and degraded sugars (such as lactose) in the prescription, it will catalyze the cross-linking process of gelatin. During the stability test, the dissolution test can be performed again by replacing the new capsule shell or new drug particles (pellet) to determine whether it is the effect of the capsule shell. In addition, studies have shown that the size of the capsule shell also affects the dissolution rate of hydrochlorothiazide during the stability test.
2) For sustained-release film coating formulations, during the aging process after the coating is completed, the external temperature promotes the cross-diffusion of adjacent polymer molecules to form a continuous coating film, and finally achieves a sustained-release effect. However, some coating materials have a low Tg (glass transition temperature). Under accelerated conditions, the coating film formed by the polymer will become denser, hindering the dissolution of the drug and slowing the dissolution.
In the stability test, especially in the accelerated test process that deviated from the normal storage conditions, the influence of the raw materials and excipients on the dissolution process of the formulation can be amplified under the conditions of high temperature and humidity for a long time. The slow drug dissolution may be caused by multiple factors. The result of the effect. When looking for the cause of slow dissolution, it is necessary to consider the physical and chemical properties of the drug, the disintegration time and method of the preparation, the size of the particles after disintegration, the wetting speed of the particles, the moisture of the preparation, the packaging material, etc., and the comprehensive analysis of the dissolution of the preparation The reason for the decrease.
[1] Drug polymorphs https://wenku.baidu.com/view/ dd6f3b768e9951e79b892719.html?sxts=1558491846268
【2】Desai, D; Kothari, S; Huang, M; Solid-state interaction of stearic acid with povidone and its effect on dissolution stability of capsules. nternational Journal of Pharmaceutics, Pub Date: 2008 Apr 1
[3] DSDesaiB.A.RubitskiJ.S.BergumS.A.Varia, Effects of various formulation factors on dissolution stability of aztreonam, hydrochlorothiazide, and sorivudine capsules; International Journal of Pharmaceutics, Volume 110, Issue 3, 26 September 1994, Pages 249-255
[4] Changes in the dissolution properties of prescription drug formulations containing gelatin; Pharmaceutical Technology APRIL 2002 :36-58
[5] https://mp.weixin.qq.com/s?src=11×tamp =1558603283&ver= 1624&signature=EggqFXyf7nqJjEkwCddrlv2LcboRgQQ9GcjbprR-JOWwHDxIYqWVTzccwmFD1LbFj35eWVTzccwmFD1LbFfIn8Uy6Thymode=1LbFfPuNUy6Thua
[6] Xue Jing, Xu Mingdi, Nan Nan, Li Yaping, The influence of raw materials and formulations on the dissolution behavior of oral solid preparations, Chinese Journal of New Drugs 2017.12
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