Pre-formulation research has gradually become a routine research project in the design and improvement of dosage forms and preparations, providing a basis for further designing dosage forms and optimizing the formulation process of preparations.
The main content of pre-formulation research work is to obtain various information required for dosage form and preparation design by consulting domestic and foreign documents or conducting experimental research, including physical properties, melting point, particle size, solubility, dissolution rate, crystal form, and pKa, partition coefficient, surface characteristics and other inherent physical and chemical properties of the drug, the stability of the drug, the compatibility of the drug and excipients, the pharmacology, side effects and irritation of the drug, and the absorption, distribution, metabolism and excretion of the drug in the body Wait.
Certain physical and chemical properties of drugs (such as drug solubility, dissolution rate, stability, etc.) and preparation operations and quality (such as powder fluidity, content uniformity, bioavailability, etc.) are often affected by particle size and particle size distribution .
Most solid dosage forms (such as powders, granules, tablets, capsules, etc.) require particle processing to improve powder properties to meet product quality and powder handling requirements. The particle size significantly affects the oral absorption of certain drugs, such as griseofulvin and spironolactone. Therefore, it is very important to understand the impact of drug particle size on formulation prescription and product effectiveness as early as possible.
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According to different particle sizes, the sieving method (pharmacopoeia sieve), sedimentation method (Coulter counter) microscopy (optical microscope, scanning electron microscope, transmission electron microscope) can be used to determine the particle size and particle size distribution of the drug.
The solubility of a drug is one of the primary factors that need to be considered in the design of drug formulations and preparations. No matter how the drug is administered, it must have a certain degree of water solubility in order to be absorbed by the body and have a therapeutic effect. Drugs with poor solubility (solubility in water<10mg/ml) often show incomplete or unstable absorption. If the solubility of the drug is lower than the expected value, it is necessary to consider adopting appropriate methods to increase its solubility.
The determination of drug solubility often uses the shake flask method. Generally, the excess drug is placed in the solvent to be measured, shaken at a certain temperature, and the drug concentration after the equilibrium is measured is its solubility. It usually takes 60 to 72 hours of shaking to reach equilibrium.
In pre-prescription research, it is often necessary to determine the solubility of drugs in multiple solvents, such as water, 0.9% NaCl solution, dilute hydrochloric acid solution (0.1mol/L HCI), and dilute alkali solution (0.1mol/L NaOH) pH6. 8 Phosphate buffer and some specific solvents such as ethanol and methanol. The solubility measured by this method is also called equilibrium solubility (equilibrium solubility) or apparent solubility (apparent solubility).
For poorly soluble drugs and their oral dosage forms, such as tablets, capsules, suspensions, and suspensions for intramuscular injection, the dissolution of the drug in the body fluid of the absorption site is the rate-limiting step of drug absorption. When dissolution is a rate-limiting process, any factors that affect dissolution will also affect drug absorption. In actual work, the in vitro dissolution test method is usually used to determine the dissolution rate of the drug to predict the dissolution and release of the drug in the body.
At present, the “United States Pharmacopoeia” (USP35) contains a variety of dissolution testing methods, including basket method, paddle method, reciprocating cylinder method, flow cell method, paddle disc method, rotating drum method, reciprocating bracket method and so on.
“Chinese Pharmacopoeia” 2010 edition two appendix stipulates 3 kinds of dissolution determination methods, including the first method (basket method), the second method (paddle method), and the third method (small cup method). Different methods and instruments can be selected according to different research and application purposes (refer to Appendix 1 of this book).
The application of dissolution testing is becoming more and more extensive, including prescription screening in the drug development stage, routine quality control of preparations, evaluation of the quality of drugs within the validity period, and prediction of the impact of drug release on drug effectiveness under different medication conditions (such as taking the medication before and after meals) , Evaluate the bioequivalence of the drug, evaluate the quality of the changed drug composition and production method after the market. In short, dissolution testing plays an important role in controlling the quality of medicines and predicting the effectiveness of medicines.
The partition coefficient (P) refers to the ratio of the concentration of the drug when it is dissolved in two immiscible solvents and reaches equilibrium. The oil/water partition coefficient (for example, n-octanol/water, chloroform/water) indicates the ratio of the drug in the oil phase and the water phase.
The dissolution, absorption, distribution and transportation of drugs in the body are related to the water solubility and fat solubility of the drug, that is, it is related to the drug oil/water partition coefficient. Generally speaking, drugs with a larger oil/water partition coefficient are easier to transport and absorb through cell membranes.
Since the solubility parameter of n-octanol is close to the solubility parameter of biofilm, it is one-half of 21.07 (J/cm³). Therefore, in order to more accurately predict the transportation of drugs in the body, n-octanol/water distribution is often used in formulation design. Coefficient, and often measured by the shake flask method.
For example, after mixing water saturated with n-octanol and n-octanol saturated with water according to 1:1, add a standard amount of drug, shake it to equilibrium at a constant temperature, and determine the drug concentration in the two phases C oil and C water Calculate the ratio C oil/C water.
If the drug exists as a monomer in the two phases, the partition coefficient is the ratio of the solubility of the drug in the two phases, and the partition coefficient can be obtained by measuring the solubility of the drug in the two solvents.
The degree of drug dissociation has an important impact on the prescription of the drug and its kinetic parameters, and it is one of the physical and chemical properties worthy of attention. Under normal circumstances, the degree of dissociation of the drug greatly depends on the pH of the drug-containing medium. In the research of prescription technology, the method of adjusting the pH of the medium is often used to make the drug ionize to a certain extent to meet the required drug solubility and formulation stability. Sex.
The degree of drug dissociation also has an important impact on the absorption, distribution, and elimination of drugs. Generally speaking, dissociated drugs are more difficult to be absorbed through biofilms, while non-dissociated drugs can often effectively pass through lipid biofilms. The relationship between the pH of the solution, the pK of the drug, and the dissociation state of the drug can be expressed by the Henderson-Hasselbalch equation.
The dissociation constant or pKa can usually be determined by potentiometric titration. According to the Henderson-Hasselbalch equation, if Ca and pKa are known, the solubility of the drug under any pH condition (the sum of the non-dissociation and dissociation solubility) can be predicted. Using the dissociation constant or pK., it is possible to predict whether the mixture will precipitate at a certain pH, and it also helps to select the appropriate salt of the drug.
Crystal (crystalline forms, polymorphs) refers to the arrangement of molecules in the crystal lattice of a crystalline substance. Drugs often have more than one crystal form, called polymorphism, or polymorphism.
Many drugs have polymorphic forms. Due to the different crystal structure of the same drug, certain physical properties such as density, solubility, and dissolution rate are different, which may affect the dissolution and absorption of the drug in the body, which may affect the clinical of the drug to a certain extent. Efficacy and safety, especially the oral solid or semi-solid dosage form of some poorly soluble drugs, the crystal form has a greater impact. In addition to polymorphic forms, drug molecules may also exist in amorphous forms, which are always more soluble than the corresponding crystalline forms.
The evaluation of polymorphs of drugs is an important pre-prescription research content. If poorly soluble solid drugs need to be made into solid oral preparations, the crystal form of the raw material should be studied, because the preparation process may cause the transformation of the crystal form of the drug.
For a new compound, you should first study whether there are polymorphs, how many crystal forms, and whether there are amorphous forms, and study the differences in physical and chemical properties of different crystal forms (such as solubility, stability), etc., determine the target crystal form, and pass Pharmacology, toxicology and clinical trials to determine the pros and cons of the selected crystal form.
If the research on the polymorphism of the drug is improper, it may cause a series of problems of the preparation variety, such as crystal precipitation, crystal form transformation, poor stability, and low bioavailability. Such as the cortisone acetate suspension for injection, if the wrong crystal form is used, agglomeration will occur after prolonged storage. For drugs with crystal forms, the crystal form inspection indicators should be set in the stability test to determine the appropriate storage conditions and ensure the stability of the crystal form.
When studying the polymorphs of drugs, the commonly used methods include hot stage microscopy, thermal analysis, and infrared spectroscopy.
Go and X-ray etc.
Hygroscopicity refers to the phenomenon that a solid surface can absorb moisture from the surrounding air. Due to the large specific surface area of the drug, most of them have different degrees of hygroscopicity.In the humid air, it is easy to absorb some moisture differently, resulting in wetting, decreased fluidity, agglomeration, liquefaction, etc., and even discoloration and decomposition. Decrease the rationale of the drug. The speed and extent of the absorption of water by the drug depends on the physical and chemical properties of the drug and the relative humidity (relathumidity, RH) of the environment.
The hygroscopicity of drugs is usually expressed by the moisture absorption balance curve, that is, the equilibrium moisture absorption of the drug is measured under different humidity, and then the subequal moisture absorption is plotted against the relative humidity. The moisture absorption balance curve of water-soluble drugs and water-insoluble drugs has a significant difference. Water-soluble drugs hardly absorb moisture when the relative humidity of the environment is lower than CRH, and when the relative humidity increases to CRH, the amount of moisture absorption increases sharply, and CRH is water-soluble Characteristic parameters of medicinal powder. Water-insoluble drugs slowly absorb moisture as the relative humidity in the air increases, and there is no critical value. The hygroscopicity of water-insoluble drug mixtures is additive.
When determining the CRH of a drug, the drug powder can be placed in an environment with different known relative humidity (such as stored in a constant temperature and humidity box or a desiccator with a saturated salt solution) for testing, and when the moisture absorption reaches equilibrium, the water absorption is calculated by weighing Weight (weight gain), the moisture absorption balance curve is obtained by plotting the equilibrium moisture absorption against each relative humidity. The relative humidity where the slope of the curve changes sharply is the CRH of the sample.
Heat, light, oxygen, moisture, pH, and excipients may all have a significant impact on the stability of the drug. Therefore, an important task before formulation design is to investigate the factors that affect drug stability. Through the study of the stability of the drug itself, it can play an important role in guiding the formulation of the formulation, the preparation process, the selection of excipients and stability additives, and the appropriate packaging design.
Drug stability test is to study the influence of heat, oxygen, moisture and light on drug stability. It can also be used to determine suitable packaging materials, storage techniques and methods.
After administration, the drug must penetrate the biofilm in the body before it can be absorbed into the human blood circulatory system. The physical and chemical properties of the drug have a great influence on its absorption. Modern pre-prescription research includes early evaluation of drug molecules permeating biofilms.
The data obtained from the physical and chemical properties of pre-prescription drugs, especially pKa, oil-water partition coefficient, solubility and dissolution rate, provide a basis for studying the possibility of drug absorption. In vitro small intestine experiment technology is often used to evaluate the absorption characteristics of drugs.
After the drug is absorbed, it is distributed to various organs and tissues of the body through blood circulation, and is eliminated from the body through metabolism and excretion. Because the drug distribution and elimination speed determine the concentration of the drug in the blood and the site of action, thereby determining the frequency of administration, it is necessary to fully understand the characteristics of drug distribution, metabolism and elimination before determining the dosage form and prescription design.
Due to the different dosage forms, different sites and routes of administration of a drug, it can affect the absorption, distribution, metabolism and excretion process of the drug in the body, resulting in different absorption speed, onset time, peak time and duration of action. See the figure below for the transport process in the body of different dosage forms of drugs, different routes of administration, and their effects on drug absorption.
In the pre-prescription research work, we should fully understand the in vivo kinetic properties and parameters of the drug itself by consulting the literature, so as to design the appropriate route of administration and dosage form.
Intramuscular injections, such as drugs, have a short or long half-life, and are generally not considered as sustained-release preparations. Another example is the oral medicine with obvious first-pass effect. Parenteral administration or nano-drug system can be used for oral administration to avoid or reduce the first-pass effect on the drug.
In the process of formulation design, it is also necessary to fully understand the pharmacology, efficacy, toxicology and other characteristics of the drug to ensure that it can maximize its efficacy and reduce toxicity in clinical applications.
Understanding the toxicological properties of drugs is very important for formulation design. The design of the preparation should be able to improve the safety of the drug and reduce the irritation or side effects. For drugs with adverse gastrointestinal reactions, it is generally not appropriate to choose oral dosage forms; if they are only irritating to the stomach, they can be designed to be intestinal-released dosage forms.
For drugs with skin irritation, skin administration should be avoided as much as possible. For more toxic drugs, a controlled release dosage form that can significantly reduce adverse drug reactions can be selected. For drugs with low therapeutic index, it is advisable to design a sustained and controlled release formulation to reduce peak and valley fluctuations, maintain a relatively stable blood concentration level, and reduce toxic and side effects.
In the process of drug formulation design, it is necessary to fully understand the mechanism of action and pharmacodynamic properties of the raw material drug, such as the site and target of the drug, the scope of the treatment window, animal models, etc., to guide the design of dosage forms and formulations.
For example, when the nitroglycerin for the treatment of angina pectoris is administered in various forms such as sublingual, transdermal, orally, the onset of action is very different from the intensity of action. If it is emergency treatment for angina pectoris, sublingual administration should be used for rapid absorption. For prophylactic long-term administration, transdermal patches are more suitable.
[1] 2010 revised edition of “Good Manufacturing Practice for Drug Quality”
[2] “Pharmacy”
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