Pharmaceutical Technology I Lecture 1 College of Pharmacy 3rd class 2016 Radhwan Al-Zidan (B.Sc. Pharm, M.Sc. Med. B. Tech.)

Pharmaceutical Technology Pharmaceutical technology is a collective term for technologies to develop candidate compounds that have either been discovered or created into commercial pharmaceutical products.

Formulation Technology involves the rational design and manufacture of dosage forms to ensure that the required biological and physical performances of the therapeutic agent are attained.

Liquids Dosage Forms / Solutions Pharmaceutical solutions are defined as liquid preparations in which the therapeutic agent and the various excipients are dissolved in the chosen solvent system. Table 1: Traditional Terms for Different Pharmaceutical Solutions

Advantages of Solutions Disadvantages of Solutions Some drugs are inherently unstable, and instability is increased when a drug is present in solution. Some drugs are poorly soluble in water. Liquids are bulky and less easy for the patient to carry compared to solid dosage forms. Liquids are also more expensive to transport, which increases the medicine’s cost. The drug is already dissolved in the solvent system, hence drug action is rapid. Solutions provide dose uniformity, and specific volumes of the liquid solutions that can be measured accurately; this allows a range of different doses to be easily administered Oral solutions are easily swallowed and are beneficial for patients for whom swallowing may be difficult, e.g. children and older people. Solutions are easier to manufacture compared to other dosage forms.

Pharmaceutical solutions may contain a range of excipients, each with a defined pharmaceutical purpose. Examples of these include: ■ the vehicle ■ co-solvents ■ surface-active agents ■ buffers ■ preservatives ■ sweeteners ■ viscosity modifiers ■ antioxidants ■ colours ■ flavours

Enhancement of Drug Solubility The solubility of a solute in a particular solvent indicates the maximum concentration to which a solution may be prepared with that solute and that solvent. The maximum possible concentration prepare a solution varies greatly and depends in part on the chemical constitution of the solute. Enhancement of Drug Solubility 1- pH Adjustment – most existing drugs are either weak acids or weak bases. In solution, an equilibrium exists between the undissociated drug molecules and their ions. The equilibrium may be represented as: Weak acid: H-A ↔ H + + A − ….. [Eq. 1] Weak base: B-OH ↔ B+ +OH −.... [Eq. 2] where [H+] and [A–] are the concentrations of the ionized form of the acid, while [HA] is the concentration of the unionized form. And [B+] and [OH–] are the concentrations of the ionized form of the base, while [BOH] is the concentration of the unionized form. Since ions are more soluble in water than neutral molecules, changing the pH of the medium to increase ionization of the drug is a common technique for increasing drug solubility in an aqueous medium. Weakly acidic drugs are ionized when the pH of the solvent is increased. Conversely, lowering pH favours ionization of weakly basic drugs. The pH required to achieve drug ionization can be calculated using the Henderson – Hasselbalch equations: Weak Acidic Drugs / pH = pKa + log ([A–]/[HA]) …..[Eq. 3] Where pH = pHp, the pH below which the free acid will precipitate out of solution.. Weak Basic Drugs /pH = pKa – log ([B+]/[BOH]) ….. [Eq. 4] Where pH = pHp, the pH above which the free base will come out of solution as a precipitate. The pH of a pharmaceutical solution is a compromise between drug solubility, stability, bioavailability, the function of excipients and physiological acceptability of the product.

2 - Co – Solvents: are often used to increase the water solubility of drugs which do not contain ionizable group(s) and whose solubility can not be increased by pH adjustment, i.e. ‘like dissolves like’. Thus, non-polar drugs are poorly soluble in water – a polar solvent. To increase the solubility of such drugs in water, the latter’s polarity should be lowered. This can be achieved by adding a third component such as a water-miscible organic liquid with a low polarity. Such a liquid, when used in this context, is called a co-solvent. Typically, a linear increase in co-solvent fraction results in logarithmic increases in drug solubility. 3 - Surfactants and Micelles - surfactants (surface active agents) and amphiphiles are molecules which have two distinct regions in their chemical structure. One region is hydrophilic and the other hydrophobic. Because of this, such molecules tend to accumulate at the boundary between two phases, such as water-air or water-oil interfaces. They reduce the surface tension of liquids, and self-assemble to form micelles once the critical micellar concentration (CMC) is reached. Poorly water soluble drugs can be solubilized in micelles to enhance their aqueous solubility. The location of the solubilisate (the drug which is solubilized within the micelles) depends on its nature. Non-polar solubilisates being located within the micelles’ hydrophobic interior cores, wheras solubilisates containing polar groups are oriented with the polar group at the micellar surface.The maximum amount of solubilisate which can be incorporated into a given system at a fixed concentration is known as the maximum additive concentration (MAC).

Complexation with Cyclodextrins: The cyclodextrins (CDs) are cyclic oligosaccharides consisting of 7, 6, or 8 (respectively) glucopyranose units. A hollow truncated cone cavity has different diameters dependent on the number of glucose units in the ring; α – CD has a cavity diameter of about 0.55 nm, β – CD about 0.70 nm and γ – CD about 0.90 nm. Many metabolically important compounds, such as lipid-soluble vitamins and hormones, have very low solubilities in aqueous solutions. A frequently used approach is to use cyclodextrin as a “carrier” molecule to facilitate the dissolution of these compounds. The hydrophilic exterior results in CDs being soluble in water. Concurrently, the less polar interior can accommodate non-polar drug molecules via non-covalent interactions, thereby allowing the non-polar drug to be ‘hidden’, thus enabling it to be molecularly dispersed in water. Thus, drug inclusion within CDs effectively increases their aqueous solubility. Each cyclodextrin molecule can form complexes with one or more drug molecules. Upon administration, for example orally, of a solution containing a drug – CD complex, the drug will be released from the CD molecule and the free drug can then be absorbed through the gastrointestinal tract. Figure 1: Structural representations of β-cyclodextrin, α-cyclodextrin, and γ-cyclodextrin.

Parts of Solvent Required for 1 Part of Solute Solubility Expression: - Table 2: Approximate Relative Terms of Solubility Pharmaceutical Solutions: - Solutions are one of the oldest pharmaceutical formulations. They are administered by many different routes. Therefore, they are often classified by the intended route (e.g. oral, otic , parenteral). Descriptive Term Parts of Solvent Required for 1 Part of Solute Very soluble < 1 Freely soluble 1 – 10 Soluble 10 – 30 Sparingly soluble 30 – 100 Slightly soluble 100 – 1000 Very slightly soluble – 10000 Practically insoluble or insoluble >10000

Table 3: Requirements of Pharmaceutical Solutions, with Respect to their Route of Administration