design of dosage forms

• To optimize the appearance of dosage is necessary to have a perfect knowledge of the physical properties of chemical ingredients formulated to dosage.

• Drug substances are rarely given as a chemical entity but is almost always given in some types of formulations.

• The initial phase of each new formulation of a preparation needed pre-formulation studies.

• Prefomulation is the assessment to gather particulars about the basic physical and chemical characteristics of the drug substance

• The purpose of preformulation is to assist in developing a stable formulation, safe and effective

Several parameters were evaluated:

1. The shape and size of particles: 2. Solubility 3. Stability 4. Polymorphic 5.Partitioning effect 6.Permeability 7.Dissolution

Data obtained from the evaluation of enhanced with data obtained from the preliminary study

• Pre-formulation research is usually conducted after a fairly active compound demonstrated useful in tests on humans

• When the pre-formulations investigated perfect, the data is record for its development

The shape and size of particles•Use of the desired form of fine powder in pharmaceutical products, one of the basic properties of physics are common all fine powder distributed•Physical properties of substances and certain chemical drugs influenced by the particle size distribution, including drug dissolution rate, bioavailability, content uniformity and stability•Characteristics of flow and sedimentation rate are also important factors related to particle size•Particle size proved to significantly affect oral absorption profile of certain drugs•Substance satisfactory uniformity in the solid dosage forms is dependent upon the particle size and distribution of the active ingredient

•Keseragaman isi yang memuaskan dalam bentuk sediaan padat sangat tergantung kepada ukuran partikel dan distribusi bahan aktif•Ukuran partikel terbukti secara bermakna mempengaruhi profil absorpsi

• There are several methods available to evaluate the particle size:

Sieving Microscopic Sedimentation

•1. Sieving - Used a series of sieves, ranging from 100 mesh to 10 mesh, sieve compiled from the largest aperture adjacent the top to the smallest aperture on the bottom. The powder is put on the top sieve done sifting the sieving machine with a speed of 150 times / min. For the powders in the range of approximately 44 microns or larger. Screening is the most widely used method.

•2. Microscopic-Optical microscopy is often the first step in determining particle size and shape to the new drug substance. Used an optical microscope, equipped with a glass object count rooms that have a certain size scale, powder under the microscope. •3. Sedimentation- Sedimentation technique using the relationship between the rate of fall of particles and size. Particles suspended in a carrier fluid is then allowed to occur precipitation. Diameter can be calculated. This method is now enhanced by using a coulter counter which can simultaneously measure the volume of the particle.

•Solubility-An important physicochemical properties of a drug substance is solubility, especially solubility in water systems.-A drug must have a solubility in water that is therapeutically effective-In order for a drug gets to a system of circulation and produce a therapeutic effect, it must first be in solution.-The compounds are relatively insoluble often showed absorption is not perfect.-If the solubility of the drug substance is less than diingikan, consideration should be given to improve the solubility.-Methods to help this depends on the chemical properties of the drug.

• For example, if the drug substance is acidic or alkaline solubility may be affected by changes in pH.

• But for many substances pH adjustment is not an effective way to improve solubility.

• In many ways it is desirable to use kosolven or other techniques Reviews such as complexation or dispersion of solids to improve water solubility.

• The solubility of the drug is usually determined by the method of equilibrium, in which the excess drug is placed in a solvent and stirred at a constant temperature for an extended period of time until equilibrium is obtained.

• Partition coefficient

A measurement of drug lipophilicity and an indication of its ability to pass through the cell membrane is the partition coefficient oil / water in systems such as octanol / water and chloroform / water.

Partition coefficient is defined as the ratio of unionized drug between the organic phase and the aqueous phase at equilibrium.

To produce a biological response, the drug molecule must first cross a biological membrane acts as a barrier fat for most drugs and allow the absorption of substances that are soluble in fat by passive diffusion, while substances that are not soluble in fat can diffuse cross the barrier with great difficulty.

The relationship between dissociation constants lipid solubility, and the pH at the site of absorption of various drugs are the basis of the theory of partitions pH

• Polymorphism Polymorphism is the ability of a compound or element to crystallize

more than one type of different crystals to obtain the drug in the two crystal forms.An important factor that formulation was crystalline or amorphous forms of the drug substance.

Forms of polymorphism usually show different physicochemical properties including melting and dissolution.

The energy required for a drug molecule to be free of a crystal is much larger than that needed to be free from an amorphous powder.

Therefore the amorphous form of a compound is always more soluble than the crystalline form.

•Changes in crystal characteristics can affect bioavailability, chemical and physical stability and has important implications for the functions the dosage form. As an example can be a significant factor with respect to the tablets because of the properties of the flow and pengkompakan•Various techniques are used in determining the properties of the crystal. The most widely used method is the hot stage microscopy, thermal analysis, spektrokopy infrared and x-ray diffraction.•Berbagai teknik digunakan dalam menentukan sifat-sifat kristal. Metode yang paling luas digunakan adalah hot stage microscopy, analisis panas, spektrokopy inframerah dan difraksi sinar-x.

Dissolution The difference in biological activity of a drug substance may be

caused by the rate at which the drug becomes available to the organism.

Dissolution is the process by which a solid substance dissolves Dissolution is a requirement that a drug can be absorbed by the

digestive tract or the liquid part of the body. In many ways the dissolution rate or the time it takes for the drug to

dissolve in the liquid at the site of absorption. For drugs that are administered orally in solid form such as tablets,

capsules or suspension, as well as drugs that are administered intramuscularly in the form of pellets or suspension.

• When the dissolution rate is the stage that determines the rate, whatever influence it will affect absorption.

• As a result of dissolution rate can affect the bioavailability of the drug from the dosage form overall.

• As previously discussed the dissolution rate can be increased by increasing the particle size of the drug, which increases the solubility in the diffusion layer.

• Ways that are most effective in obtaining the dissolution rate is to use a water-soluble salt of the parent substance.

• Permeability Assessment modern prefomulasi includes inputs beginning of the

passage of drug molecules across biological membranes. The data obtained from the study of physics-chemistry, solubility and

dissolution rate gives an expected absorption.

• Stability• One of the most important activities in preformulasi work is the

evaluation of physical-chemical stability of the pure substances.• Assessment of the stability of which is connected in the phase of pre-

formulation, including the stability of the drug itself in the solid state, solution phase stability and stability in the presence of substances is expected.

• Chemical instability of the drug substance can take many forms, because the drugs used today are diverse chemical constituents.

• In chemical drug substance is alcohol, phenols, aldehydes, ketones, esters, acids, salts, alkaloids, glycosides and others, each with relative chemical groups that have different tendency to chemical instability.

• In the chemical process of damage is most often include hydrolysis and oxidation.Hydrolysis is a process solvolysis where drug molecules interact with water molecules to produce a product fractions with different chemical structures.

• For example, aspirin or acetyl salicylic acid in combination with a water molecule and hydrolyze into one molecule of acetic acid.