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302 Pharmaceutical Chemistry
Melting point: Melting point of sorbic acid is 130-132°C.
Uses:
(1) It is well known as a fungistatic agent for food products, especially cheeses. (2) It is mostly used as a mold and yeast inhibitor in pharmaceutical preparations.
EXPERIMENT NO. 12.10
Aim: Preparation of magnesium silicate
Reaction:
SiO3 (aq) + MgCl2+2O (aq) o 0J2Q6L22[+2O (s) + 2NaCl (aq)
Na
2
Or
2MgSO
Magnesium trisilicate contains not more than 29% of magnesium oxide and not more than 65% of silicon dioxide both calculated with reference to the ignited substance.
Reagents: NaOH MgSO HCl Acetone Preparation: It is prepared by precipitation from solution of sodium silicate and magnesium
sulphate or magnesium chloride. Preparations are as follows:
(i) Preparation of sodium silicate solution: The silicate solution is prepared according
(ii) Preparation of magnesium silicate: The synthesis procedure of magnesium silicate
+ 2Na226L22 + xH2O o 0J26L22[+2O + Na2SO4 + H2O
4
+2O or MgCl2+2O
4
to the method of Kalapathy, Proctor & Shultz (2000). The wheat husk obtained from a flour factory is burnt in open air with a hand-lighter. Semi-burnt wheat husk is burnt again in an incineration furnace (Protherm, Turkey) at 600°C for 5 hours because it is known that ashes with high silica content are obtained at temperatures lower than 400°C (Kamath and Proctor, 1998). Ozgul-Yucel et al. (2004) also demonstrated that rice husk ash has an amorphous structure when burnt at 600°C. Thus, 600°C is chosen as the burning temperature. 100 gm of ash is placed into a 2 L flask, 600 millilitres of 1 M sodium hydroxide solution was added, and the flask is capped with a watch glass. The mixture is boiled for 1 hour with constant stirring using a magnetic stirring bar. Then the mixture is filtered under vacuum, and the upper carbon residues are washed with 50 mL of hot water to separate clear sodium silicate solution from carbon residues (Ozgul-Yucel et al. 2004). The silicate solution is preserved in a plastic bottle until used. Determination of silica content of the sodium silicate solution is achieved by lowering the pH of the solution from 12 to 7 to precipitate silica. After filtration, silica solution is double washed with 100 mL of water, dried at 110°C for 12 hours, and weighed (Kamath and Proctor, 1998).
powder is given in Fig. 12.1. Production of magnesium silicate consists of four steps,
Experiments 303
reaction, filtration, washing to eliminate impurities, and drying at room temperature.
Production of magnesium silicate takes place at 25°C or 50°C using two types of
magnesium salts (MgCl
+2O or MgSO4+2O). A stoichiometric quantity of
2
magnesium salt is completely dissolved in distilled water and is poured into a
double-jacketed 350 mL reactor. Then the sodium silicate solution (Na
SiO3) is
2
added via a peristaltic pump (Heildolph Pumpdrive 5201, Germany) at a feeding
rate of 0.6 mL/min, 35 mL/min, or 70 mL/min. During the reaction, a mechanical
stirrer constantly stirs the solution. After the reaction is completed, the mixture is
filtered under vacuum. The residual magnesium silicate on the filter paper is
washed with 500 mL of distilled water to remove impurities. In only one experimental
set is the upper part is washed with 200 mL of acetone after washing with 500 mL
of water to see the effects of polar solution on the production of magnesium silicate
to eliminate organic impurities. The solid part, which is obtained by filtration, is
dried at room conditions and came to balance. For production from wheat husk ash, 25 mL sodium silicate solution (4.17 gm wheat
husk ash, containing 2.44% SiO
 +
O, and 75 mL dissolving water is used in each batch. The amount was
2
), 4.242 gm of MgCl2+2O or 5.166 gm of MgSO4
2
calculated stoichiometrically according to the reaction mentioned above. Properties: Fine, white, odourless, tasteless powder, free from grittiness. Magnesium
silicate hydrate is a compound of magnesium oxide and silicon dioxide with varying amount of water.
MgCl . 6H O or
MgSO . 7H O solution
22
42
Fig. 12.1: Production of MgO . nSiO2 . xH2O powder in each batch
Na2SiO3solution (25 mL)
Reactor (25°C or 50°C)
MgO . nSiO . xH O
MgO . nSiO . xH O
Drying (at room temp.)
Dry white MgO . nSiO . xH O
22
precipitation
Filtration
Washing
22
22
Distilled water 25°C, 500 mL
304 Pharmaceutical Chemistry
Test for identification: For magnesium: To the solution of sample, add dilute nitric acid solution. A white
precipitate is produced that is redissolved by adding 1 mL of 2M ammonium chloride. Add 0.25M disodium hydrogen phosphate, then a white crystalline precipitate is produced.
For silicate: In a lead or platinum crucible mix by means of a copper wire to obtain a thin slurry, the prescribed amount (0.25 g) of substance with 10 mg of sodium fluoride and a few drops of sulphuric acid cover the crucible with thin transparent plate of plastic under which a drop of water is suspended and warm gently within a short time. A white ring is formed around the drop of water.
Assay: For magnesium oxide: Weigh accurately 1 gm substance and dissolve in 35 mL of water;
allow standing for 15 minutes in water bath. Cool the contents to room temperature; filter and wash the residue with water and dilute the combined filtrate and wash with 250 mL water. Neutralize 50 mL of this solution with about 8 mL of 10M NaOH and then add 10 mL ammonia buffer pH 10, 50 mg mordant black II mixture. Heat the contents to 40°C and titrate with 0.05M disodium EDTA until colour changes to deep blue. Each mL of 0.05M
GLVRGLXP('7$ŋJ0J2
For silicon dioxide: Weigh accurately 0.7 gm of substance, add 10 mL of 1M sulphuric acid, 10 mL water and heat in water bath for 1.5 hours. Shake frequently and replace the evaporated water. Allow to cool; decant on to an ashless filter paper (7 cm in diameter). Wash the precipitate by decantation with three quantities each of 5 mL of hot water, transfer it to the filter paper and wash it with hot water, until 1 mL of the filtrate remains clear on addition of 2 mL of barium chloride solution and 0.5 mL of 2N HCl. Ignite the filter paper and its contents in a tarred platinum crucible at 900°C to constant weight. The residue is silicon dioxide.
Uses: It is used as non-systemic antacid and adsorbent.
13
Multiple-Choice Questions and Answers
1. Which of the following statement best describes pharmacodynamics?
(a) The study of how drugs reach their target in the body and how the levels of a
drug in the blood are affected by absorption, distribution, metabolism and excretion.
(b) The study of how drugs can be designed using molecular modelling based on the
drug’s pharmacophore.
(c) The study of how a drug interacts with its target binding site at the molecular
level.
(d) The study of how functional groups are important in binding a drug to its target
binding site and the identification of a pharmacophore.
2. Highly polar drugs: (a) Obey Lipinski’s rule of five (b) Are well absorbed through the gut wall (c) Are taken parentally (d) Are taken orally
3. According to Lipinski’s rule of five, oral drugs should have all the following except: (a) Molecular weight less than 50 (b) No more than 5 hydrogen donor groups (c) No less than 5 hydrogen acceptor groups (d) A calculated log P value more than +5
4. Oral drugs should have the following requirements except: (a) Sufficient water solubility (b) Obey Lipinski’s rule of five (c) High lipid solubility (d) Sufficient stability towards metabolic enzymes)
5. All of the following organs are responsible for drug excretion except: (a) Pancreas (b) Kidneys (c) Sweat glands (d) GIT
306 Pharmaceutical Chemistry
6. First pass effect means: (a) Drug is bound to plasma proteins (b) Drug distributes into interstitial fluids (c) Drug undergoes enzyme-catalyzed reactions in the liver (d) Drug interacts with its receptor
7. Which of the following is correct for drug absorption? (a) It studies the mechanisms by which the drug reaches the blood supply. (b) It is all the biochemical reactions the drug undergoes in the body. (c) It is the ways of removal of the drug from the body. (d) All of the above
8. Which of the following helps to prolong the duration of action of drugs in the body? (a) Strong binding to plasma protein (b) High distribution into fatty tissues (c) Slow metabolism (d) All of the above
9. Drug absorption depends on the following factors except: (a) Method of drug administration (b) Drug hydrophilic/hydrophobic solubility (c) Chemical stability of drug in the stomach (d) High distribution into fatty tissues
10. Nonpolar drugs: (a) Are easily excreted as such in urine (b) Are reabsorbed into blood (c) Are not excreted into the bile (d) Are not excreted in sweat
11. Highly nonpolar drugs: (a) Are soluble in GIT secretions and blood (b) Are soluble in fat globules in GIT (c) Are poorly absorbed by the gut (d) Both (b) and (c)
12. Which of the following needs to be established before the search for a lead compound
takes place? (a) The pharmacophore (b) Structure-activity relationships (c) A bioassay (d) Patents
13. In drug design, we may increase the susceptibility of the drug to metabolic reaction in case of:
(a) Drug toxicity (b) Lingering side effects (c) Drug tolerance (d) Both (a) and (b)
Multiple-Choice Questions and Answers 307
14. Drugs are given by IV injection because all of the following except:
(a) They are hydrolyzed by acid of the stomach (b) They are highly polar to be absorbed from the gut wall (c) They are sufficiently nonpolar to be absorbed from the gut (d) To have rapid onset of action
15. All of the following are factors affecting drug dosage except:
(a) Pharmacokinetic parameters of drug (b) Drug tolerance (c) Dosing time, drug-drug interactions (d) Obesity and race
16. Frequency of doses is estimated by knowing:
(a) Therapeutic index of the drug (b) Amount of drug per dose (c) Half-life of the drug (d) Partition coefficient of the drug
17. You can easily tell that a drug is a natural product because:
(a) You can’t tell just by looking at its structure (b) Its structure contains lots of chiral centres and is very complex (c) Its structure is very simple (d) None of the above
18. All new ‘prescription only’ medicines must be issued with a marketing authorisation
from the MHRA before they can: (a) Undergo phase I clinical trials (b) Undergo phase III clinical trials (c) Be advertised to the public (d) Be advertised to prescribers
19. What is meant by a lead compound in medicinal chemistry? (a) A drug containing the element lead. (b) A leading drug in a particular area of medicine. (c) A compound that acts as the starting point for drug design and development. (d) A drug which is normally the first to be prescribed for a particular ailment.
20. To compare the safety of one medicine with another medicine, it would be necessary
to (a) Review the evidence from phase I clinical trials. (b) Review the evidence from phase II clinical trials. (c) Review the evidence from a post marking clinical trial. (d) Review the number of reports obtained from the yellow card adverse drug
reaction reporting scheme.
308 Pharmaceutical Chemistry
21. What does the symbol P represent in a QSAR equation? (a) pH (b) Plasma concentration (c) Partition coefficient (d) Prodrug
22. What is the symbol S in a QSAR equation? (a) The hydrophobicity of the molecule (b) The electronic effect of a substituent (c) The substituent hydrophobicity constant (d) A measure of the steric properties for a substituent
23. Which of the following characteristics is detrimental to oral activity? (a) Stability to digestive enzymes (b) Susceptibility to metabolic enzymes (c) Stability to stomach acids (d) Solubility in both aqueous and fatty environments
24. Which of the following is one of the rules in Lipinski’s rule of five? (a) A molecular weight equal to 500 (b) No more than five hydrogen bond acceptor groups (c) No more than 10 hydrogen bond donor groups (d) A calculated logP value less than +5
25. What is the term used for the automated in vitro testing of large numbers of
compounds using genetically modified cells? (a) Robotic testing (b) High throughput screening (c) Multi-screening (d) Nanotechnology
26. Some orally active drugs do not obey the rule of five. For example, some drugs with molecular weights greater than 500 are found to be orally active. Which of the following mechanisms is the most likely reason for this?
(a) Transport by transport proteins (b) Passage through pores between the cells of the gut wall (c) Pinocytosis (d) Ion channels
27. SRPM (Structural, Receptor interaction, Pharmacokinetics, Metabolism) refers to
(a) Random screen (b) Changes resulting from bioisosteric replacements (c) Classical isosteres (d) Causes for disease states in rational screen
Multiple-Choice Questions and Answers 309
28. Some orally active drugs do not obey the rule of five. For example, some highly polar
drugs with a molecular weight less than 200 are found to be orally active. Which of
the following mechanisms is the most likely reason for this? (a) Transport by transport proteins (b) Passage through pores between the cells of the gut wall (c) Pinocytosis (d) Ion channels
29. Which of the following statements is false with respect to NMR screening to detect drug-target interactions?
(a) The procedure relies on small molecules (drugs) having shorter relaxation
times than large molecules (targets).
(b) The procedure can be used on mixtures of compounds. (c) The method can detect weak binding. (d) The method can identify small molecules binding to different regions of the same
binding site.
30. Which of the following does not have an effect on adsorption from solution onto a solid adsorbent?
(a) Solubility level of the solute (b) Absorption capacity (c) Temperature of adsorption medium (d) Surface area of the adsorbent
31. Which of the following statements is false regarding the blood brain barrier?
(a) The walls of the capillaries supplying the brain have tight fitting cells making it
difficult for polar drugs to leave the capillaries.
(b) The capillaries in the brain have a fatty coating making it more difficult for drugs
to enter the brain.
(c) The walls of the capillaries supplying the brain are made up of several layers
of cells, which act as a barrier to the release of drugs.
(d) Hydrophobic drugs pass through the blood brain barrier more easily than
hydrophilic drugs.
32. Which of the following statements is the closest description of Phase I metabolism?
(a) Reactions which add a polar molecule to a functional group already present on
a drug or one of its metabolites. (b) Reactions which occur in the blood supply. (c) Reactions which add a polar functional group to a drug. (d) Reactions which occur in the gut wall.
310 Pharmaceutical Chemistry
33. There are several sources and methods of discovering new compounds. Which of the following is most likely to lead to the discovery of a complex structure quite unlike any other previously discovered?
(a) Combinatorial chemistry (b) Database mining (c) Screening plant extracts (d) Me too drugs (also known as prototype drugs)
34. Metabolites produced from the respective drugs are screened for the same or other activities as well; however, they can also have a different pharmacological profile other than the drug.
(a) Drug candidate (b) Drug metabolism studies (c) Brief mechanism of penicillin (d) Sulfamide antimicrobial agent
35. Which of the following statements is the closest description of Phase II metabolism?
(a) Reactions which add a polar molecule to a functional group already present on
a drug or one of its metabolites.
(b) Reactions which occur in the blood supply. (c) Reactions which add a polar functional group to a drug. (d) Reactions which occur in the gut wall.
36. What does MR represent in a QSAR equation?
(a) Molar refractivity is a steric factor (b) Molar refractivity is an electronic factor (c) Molar refractivity is a hydrophobic factor (d) Molar refractivity is a stereoelectronic factor
37. Which of the following statements is not true when comparing 3D QSAR with conventional QSAR?
(a) Only drugs of the same structural class should be studied by 3D QSAR or
QSAR.
(b) 3D QSAR has a predictive quality unlike QSAR. (c) Experimental parameters are not required by 3D QSAR, but are for QSAR. (d) Results can be shown graphically in 3D QSAR, but not with QSAR.
38. What is a semi-synthetic drug?
(a) A drug made entirely from scratch in a lab. (b) A drug which has been partly made by nature and partly in a lab. (c) The structure of a drug half-way through its preparation. (d) A drug isolated from nature and used without any further modification.
Multiple-Choice Questions and Answers 311
39. Which of the following is not an endogenous lead compound?
(a) Neurotransmitter (b) Alkaloid (c) Hormone (d) Modulator
40. Which of the following is not an endogenous compound?
(a) Dopamine (b) Endorphins (c) Noradrenaline (d) Desipramine
41. Natural products are often used as lead compounds in the design and synthesis of
novel drugs. Which of the following general characteristics of a natural product is
most likely to be a disadvantage in synthesising analogues? (a) Novelty of structure (b) Complexity of structure (c) Level of activity (d) Availability
42. What is ‘simplification’ when referred to in drug development terms?
(a) The process of adding more chiral centres to a compound to make it bind more
easily to its biological target.
(b) The process of removing unimportant groups from a lead compound in the
hope of maintaining activity but rendering the resulting compounds cheaper and easier to make.
(c) The process of shortening the drug development process from the discovery
stage to its clinical trial stage.
(d) The process by which a drug candidate is synthesised as simply as possible.
43. Which of the following drugs was inspired by nature? (a) Morphine (b) Salbutamol (c) Paclitaxel (d) Erythromycin
44. Which of the following statements is true? (a) There is no general rule regarding the relative size of drugs and their targets. (b) Drugs are generally smaller than drug targets. (c) Drugs are generally larger than drug targets. (d) Drugs and drug targets generally have similar molecular weights.
45. What is meant by a binding site? (a) The area of a macromolecular target that is occupied by a drug when it binds. (b) The portion of the drug to which a drug target binds. (c) The bonds involved in binding a drug to its target. (d) The functional groups used by a drug in binding to a drug target.
46. Which of the following binding interactions is likely to be the most important initial
interaction when a drug enters a binding site? (a) van der Waals interactions (b) Induced dipole-dipole interactions (c) Ionic (d) Hydrogen bond