Generic Cialis (Tadalafil)


This invention relates to compressed solid dosage forms, such as tablets and caplets, and methods for their preparation. More specifically, the invention relates to tabletting methods and tablets of medicaments obtained therewith with low water solubility, such as, for example, tadalafil.


In many cases, when solid dosage forms are administered orally, the drug must be dissolved in aqueous gastric juice, for example, in the patient's stomach, before the drug can show a therapeutic effect. An unresolved problem with compressed solid dosage forms for oral administration, such as tablets and caplets (ie, capsule-shaped tablets), is that the rate of dissolution of certain drugs from the dosage form limits their bioavailability. This problem is especially common for drugs, which are small organic molecules with low solubility in liquids containing water.

There are several ways to overcome the solubility problem of poorly soluble drugs. For example, the drug itself can be modified. The physical form of the drug can be varied by various techniques to optimize the rate at which the drug is dissolved. Of these techniques of greatest importance in this invention is particle size reduction. The rate of dissolution of a solid can often depend on the surface area that is exposed to the dissolving medium; and since the surface area of ​​a given mass of substance is usually inversely proportional to the particle size of the substance, reducing the particle size of a powdery or granular substance can increase its dissolution rate.

When effective, particle size reduction increases the rate of dissolution of the comminuted solid while increasing the surface area that is exposed to the dissolving medium. However, particle size reduction is not always effective in increasing the dissolution rate of the drug in the compressed solid dosage form. During the manufacturing process of the dosage form, many hydrophobic drugs have a strong tendency to agglomerate into larger particles, resulting in a complete decrease in effective surface area. Remington's monograph (The Science and Practice of Pharmacy, 20th ed. 656, 657, AR Gennaro Ed., Lippincott Williams & Wilkins, Philadelphia 2000), which is incorporated herein by reference, provides a more complete discussion of effective surface area. and the effect of particle size on solubility. A drug that appears to have been ground to a fine particle size will sometimes exhibit solubility properties that are characteristic of larger particles due to agglomeration or the like.

There are three known methods for the production of compressed solid dosage forms: the wet granulation method, the double compression method (also known as dry granulation), and the direct compression method. Each of these methods includes a mixing step that can stimulate the agglomeration of the finely divided drug particles into larger, less rapidly dissolving particles.

In the wet granulation method, a pre-weighed drug and one or more other ingredients such as a diluent are mixed. The mixture is then mixed with a liquid such as water or ethanol, which causes the particles to agglomerate into a wet mass. The liquid may contain a binder. The wet mass is sieved to obtain granules, which are subsequently dried. The dry granules are sieved to obtain granules of a predetermined size. The granules are then usually mixed with a solid lubricant and possibly other ingredients. Finally, the granules containing the lubricant and any other additional granular ingredients are compressed into a tablet, which can then be coated.

The double compression or dry granulation process has fewer steps than wet granulation and does not require liquid contact or drying, making the process suitable for water- and heat-sensitive drug preparation technology. In the double compression method, the drug and other ingredients such as a lubricant are mixed and then compressed in a first compression step. There are two convenient primary pressing techniques. One is compaction with a roller press, in which the mixture is fed between rollers, which compress the mixture into plates; the other is an agglomeration in which the mixture is compressed into an agglomerated mass that has a tablet-like shape that is usually larger than tablets intended for human consumption. The resulting flakes or agglomerated mass is then converted to granules, mixed with a solid lubricant and compressed in a second compression step to form the final tablet.

The direct compression method is the simplest of the three known methods for producing compressed solid dosage forms. In the direct compression method, the drug and any other ingredients are mixed together and directly compressed into the final tablet. Tablet ingredients must have good flow and cohesion characteristics to be suitable for direct tablet compression. Microcrystalline cellulose and lactose are two commonly used diluents in direct tablet compression.

In the development and manufacture of pharmaceutical compositions of drugs with poor water solubility, when its high bioavailability is required, a combination of a drug with a small particle size (such as, for example, finely divided particles of a drug) and an appropriate manufacturing method (for example, one of the above-described methods ). The fine grinding process, however, can be costly in terms of time and productivity of the process, and can also pose a safety problem, as the fine grinding process can result in a finely divided drug powder.

Thus, any new composition and / or manufacturing process that provides suitable dissolution and bioavailability rates when using relatively large drug particles may provide safer and more cost effective methods for the production of solid dosage forms.

Tadalafil, the active ingredient in Cialis®, has been used to treat erectile dysfunction in men. Instructions for use of the Cialis® preparation describes this product as almond-shaped film-coated tablets for oral administration containing tadalafil and the following inert ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline lacryl cellulose, sodium lacrylate, titanium dioxide and triacetin (see Cialis-Pi.pdf).

Tadalafil has a chemical name - (6R-trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12а-hexahydro-2-methyl-pyrazino [1 ', 2' : 1,6] pyrido [3,4-b] indole-1,4-dione.

The structure of tadalafil (CAS # 171596-29-5) is given below:

tadalafil sctructure

Tadalafil is a solid that is practically insoluble in water and very slightly soluble in some organic solvents such as methanol, ethanol and acetone. US Pat. No. 6,841,167 teaches that the solubility of tadalafil in water is approximately 2 μg in 1 ml of water at 25 ° C.

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