Raw material and technology to dissolution of solid preparations I
Writer： admin Time：2020-04-24 11:06 Browse：℃
1. Overview
It is known that physical and chemical properties of medicine itself are important factors affecting its dissolution, and formulation and technique will also lead to some effects in different degree. They will then together influence medical absorption in human body. However, China’s pharmaceutical industry is weak in material control, formulation, technique and production. Therefore, producers can gain information about materials, formulation and technique as much as possible during their research. They should also make it clear that how these factors influence medicine dissolution so that their products can pass evaluation successfully. On the basis of previous papers, a summary is made on the influence of medical material crystal and granularity, auxiliary type and dosage, medical material powdering technology and tablet preparing technique on dissolution of oral solid preparation.
2. Medical material crystal and granularity
Polymorphic medicines can have different physical properties (such as melting point, solubility) and stability due to their variable crystal structure. Among them, solubility difference will have apparent influence on properties of preparations, especially on dissolution of insoluble oral solid. Then the absorption in body will be also influenced. Therefore, for polymorphic oral solid, necessary research on medicine crystal can be carried out during R&D of products. Such a action can not only help select out the useful crystal to preparation processing technique or clinical therapeutics, also avoid clinical unsafety or efficacy reduction caused by crystal type. Therefore, producers can read patent, instruction and research literature on crystal form of the preparation compound, detect the preparation and monitor crystal form change during processing and research on stability.
In a research, the dissolution curve of rifampicin oral solid is plotted. Crystal forms of rifampicin can be classified into type I, type II, and amorphous. Its form is mainly determined by the crystalline solvent. Type I and type II are both effective forms. Type I crystal appears red. It is not oxidized easily, and its molecular symmetry is better. Its good efficacy also makes it the widely used drug substance of rifampicin in China. Besides, Orange Book of FDA and Orange Book of Japan both recommend type II crystal as the reference preparation. In the research, the dissolution curves of type I rifampicin tablets/capsules and type II rifampicin tablets/capsules in solvent of three different pH values are plotted and compared. The result shows that these curves are apparently different, while the different hardly has something to do with crystal form. The difference is mainly caused by the disintegration time, i.e. techniques. However, since the final products are produced by the same company, influence of techniques is excluded. Therefore, it can be summarized that the difference of curves are related with crystal forms. It can be predicted that it is difficult to make dissolution curve of domestic generic drugs consistent with that of original drugs or similar drugs recognized by the world, if the material source of generic drugs is not changed. While for quality evaluation, whether generic drugs’ dissolution curve in variable solvent should keep the same with reference preparation is still doubtful. For example, if dissolution curve is different when the solvent pH is different from the pH value of digestive juice for drug digestion, can this result be used to prompt the high risk of the drugs in bioequivalency (BE) test, but not as the basis of quality inconsistency.
Researchers also studied on the influence of amoxicillin drug substance on dissolution. In the research, three substances of three crystal forms produced by three enterprises (A, B, C) are studied. They are processed to capsule in the same formulation and then dissolution curves are compared. The result shows that the crystal forms of these drug substances are micro square needle-like crystal/columnar crystal, columnar crystal and needle-like crystal respectively. And the curves are apparently different. Capsules made from drug substances of enterprise A and B can dissolve quickly. Their cumulative dissolution rate approaches 80% in 5min. One possible reason is that needle-like crystal is not advantageous to preparation dissolution. It is suggested that drug substance crystal form can be studied during evaluation. Some other scientists also studied on the influence of different crystal forms on roxithromycin dissolving speed and rate. Influenced by crystalline solvent and technique, roxithromycin can generate three crystal forms. The drug substance of roxithromycin crystalized in acetone dissolves slowly and its capsules will also dissolve slowly. However, if crystalized in methanol, roxithromycin can generate two crystal forms due to different crystalizing techniques. One crystal and its capsule can dissolve quickly, while the other’s dissolution speed is similar to that of crystal in acetone.
Another research is the relation between sulpiride tablets dissolution and its materials. Impure materials (contains impurity and mixed crystals) will have lower melting point and wider melting point difference. It is generally thought that materials are purer whose melting point difference is less than 1°C. The researchers applied sulpiride materials from different batches of the same producer. During experiment, the dissolution rate of these tablets in 0°C approaches 100%, but the rate decreases quickly when the test of one group is speeded up. Through detection, it can be found that sulpiride of this batch is of low melting point and wide melting point difference. After the second crystallization, its content hardly changes but melting point different apparently narrows and its melting point approaches that of other materials in the other two groups. This finding indicates that the difference of melting points and melting point difference has nothing to do with foreign matters but mixed crystals.
In summary, polymorphic drugs of generic drugs are not required to have the same crystal form with comparison drugs in current evaluation. Also, the consistency of their crystal forms can help improve the passing possibility of BE test. Therefore, producers can check and retrieve more information about crystal of compassion preparation and applies multiple analysis methods, such as X-ray diffraction of single crystal, X-ray diffraction of powders, polarization microscope, thermal analysis (thermogravimetric analysis, differential scanning calorimetry), spectroscopy (infrared spectrum, Raman spectrum, solid nuclear magnetic resonance) to detect crystal forms. Besides, some factors should be monitored, such as temperature and humidity during drying, grinding, powdering, wet granulation, spraying drying and tablet press, and crystal form change during stability research. Especially when sub-stable crystal is selected to increase dissolution and improve bioavailability, some proper measures should be taken to prevent medicines from transforming from sub-stable to stable during storage.
Except crystal form, granularity is another influential property. Generally speaking, smaller granules have larger specific surface areas, larger contacting areas with medium, and higher dissolving speed. Especially for insoluble oral solid, its dissolution is actually a slow digestion process. Therefore, granularity might have something to do with medicine digestion in human body. As a result, during evaluation of generic drugs, granularity of drug substance cannot be ignored.
Another research on the relation between Acotiamide drug substance size and Acotiamide tablets dissolution. The researcher screened out proper substance size based on dissolution speed before determining formulation. After determining formulation, the original drug of this substance was used as reference preparation. Four dissolution curve of solvent is the main index and an evaluation was made on these curves. The final result shows that among granules of Acotiamide screened through 120, 200, 300 and 400 meshes, samples of 400 meshes (D90≤20μm) all dissolve in proper speed in multiple medium. And the tablets made by these samples have the same dissolution with the original products in 4 dissolving medium.
Influence of Medroxyprogesterone 17-acetate granularity on dissolution rate is also tested. In experiment, Medroxyprogesterone 17-acetate substance is grinded and screened though a screen of 60, 80, 100, 140 and 160 meshes to prepare drug substances of different granule size. They are then made to capsules according to the same technique. The original product of Medroxyprogesterone 17-acetate is used as the reference preparation. 900ml water (containing 0.5%SDS) is the dissolving medium. Then the similarity of dissolution curves is observed. The result show: Dissolution rate of Medroxyprogesterone 17-acetate increases as drug size reduces. The drug substances through screen of 100 meshes have the same dissolution curve with original products. What should be pointed out is that the original drug is tablet while the generic drug is capsule. Therefore, evaluation of such a modified product should be carried out in accordance with General Considerations for Evaluation of Modified Drugs (Common Oral Solid Preparations) in Evaluation of Quality and Efficacy of Generic Drugs (Draft for Comments).
Influence of granule size on Cefidipine granule dissolution is also studied. Cefidipine substance of the same batch is used. Two groups are sized to D90:142.90μm, 50:30.25μm and D10:3.47μm (100-mesh screen) and D90:51.21μm, D50:10.71μm and D10:2.25μm (200-mesh screen) respectively. Another group is grinded and powered to granules of size of D90:35.62μm, D50:6.98μm and D10:1.66μm. According to determined formulation, drug substances of three sizes and quantitative auxiliary are prepared. Original product of Cefidipine is used as reference preparation. Through comparison, the similarity of their dissolution in solvent is shown. Drug substances of different size have different dissolution rate. The granules made from the two group substances screened in standard method are different from reference preparation in their dissolution in different solvents, while granules of the other one group are consistent with the reference preparation. Therefore, it is apparent that granule size reduction of Cefidipine can effective increase its dissolution rate.
