Download - Practical Medicinal Chemistry - Manspharfac.mans.edu.eg/media/clinic_main_menu/news_1541436659.pdf · Clinical Pharmacy Programe Practical Medicinal Chemistry PC609 Third Level 2015

Clinical Pharmacy Programe

Practical Medicinal Chemistry

PC609

Third Level

2015 – 2016

Prepared by

Staff Members of Medicinal Chemistry Department

Clinical Pharmacy Practical Handouts (PC 609) 2015/2016

Medicinal Chemistry 1

Subject index

Subject page

Intended Learning Outcomes of courses (ILO's) 3

Part 1: Drawing standards of chemical structures 4

Part 2: Physicochemical properties of drug action 34

Acid/base properties 34

Predicting degree of ionization of drug molecule 38

Hydrophilic/lipophilic properties 42

The hydrophobicity constant 46

Case study 50

Part 3: Case study "Antifungal Drugs" 58

Part 4: Titrimetric determination of pharmaceutical preparations 62

Penicillins: Benzylpenicillin 62

Cephalosporins: Cephalexin 64

Sulfonamides 66

Determination of ZnSO4/Sulfacetamide sodium 68

Assay of zinc undecenoate 71

Propylparaben 73

Betadine 75

Isoniazide (INH) 77

Busulphan 97

Problems 81

Evaluation sheet 84



Evaluation of the Practical pharmaceutical chemistry

PC609

The 25 Marks of practical course will be distributed as following:

The total degree of practical course 25 Marks

ChemBioDraw exam 8 Marks

Physicochemical exam 5 Marks

Assay exam 5 Marks

Quiz on assay 3 Marks

Behavior and attendance 3 Marks



Intended Learning Outcomes of courses (ILO's)

Upon completion of the course the student should be able to:

1. Draw chemical structures in two and three dimension using ChemDraw

program.

2. Draw diagrams and sketches of different equipment and glassware used in

chemical reactions using ChemDraw program.

3. Explore in detail some further useful application of ChemDraw program.

4. Understand the relationship between the chemical and physical properties of

related compound and their medicinal use and pharmacological activity.

5. Handle laboratory chemicals in a correct and safe way to obtain optimum

results without harmful effects.

6. Perform titrimetric techniques for determination of some pharmaceutical

compounds, handling data in term of graphical presentation.

7. Be familiar with the analysis of drugs and the laboratory techniques used for

that.

8. Analyze pharmaceutical dosage forms and determine their active constituents

by different analytical methods.

9. Identifying the drug impunities and different related substances and giving

possible explanation of their existence.



PART 1

Drawing Standards of Chemical Structures Overview

The information required to begin using Chem Draw includes how to do the following:

Start Chem Draw.

Create, open, and save documents.

Identify the parts of the Chem Draw interface.

Drawing the different chemical structures and showing the chemical properties,

stereochemistry, fragmentation pattern, 1H-NMR, …..etc..

Drawing the synthesis, degradation and metabolic pathways of the drugs.

Interpretation of the mode of actions of drugs and drug receptor interaction in

diagram form.

Basics drawing using Chem Draw

Starting Chem Draw

You can start the Chem Draw application in the following ways:

From the desktop, double-click the Chem Draw icon, or:

From the Start menu, choose Chem Draw, where a new document is created.

The Work Area:

The work area appears whenever you launch Chem Draw. By default, the work area

displays commonly used toolbars, the main menu, and document status bar. The

work area appears below:



Optional Toolbars

ChemDraw provides a number of optional toolbars and information windows to

facilitate production of ChemDraw documents. These toolbars are accessed from the View

menu. They are divided into three basic groups:

Standard Toolbars and Show Windows

Tool Palettes

Templates

Showing and Hiding Toolbars

To show or hide a toolbar:

From the View menu, select a toolbar.

A check mark appears next to the item when the toolbar is displayed.



Docking and Undocking Toolbars

The standard toolbars, can be docked or undocked. Docked toolbars can attach to any edge

of the ChemDraw window. Undocked toolbars can float anywhere in the ChemDraw screen.

To dock a toolbar:

Drag the toolbar to the edge of the ChemDraw screen where you want it to dock.

Double-click the toolbar background. This wil dock the toolbar in the default

position.

To undock a toolbar:

Drag the toolbar into the position you want.

The Main Toolbar

Most common tools are on the main toolbar. These include all tools necessary to draw

and edit structures, reactions, and shapes. Go to View>Show Main Toolbar.

The main toolbar has other toolbars extending from it. You can “tear off” these smaller

tool bars and place them anywhere on your screen. To tear off a toolbar:

1. Click the arrow on the lower right of a tool in the main toolbar.

2. While holding the mouse button down, point to the title bar, and release the button.



Opening Documents

To open a document, do one of the following:

Go to File>Open. In the Open dialog box, select the name and location of the file and

click Open.

In the File menu, choose the document from the list at the bottom.

Saving Documents

Go to File>Save; Choose a folder in which to store the file.

Type a file name in the Save As text box.

Select a file format then Click Save.

Selecting Objects

Use the Lasso or the Marquee tool to select any object. You use the Lasso for freehand

selection and the Marquee to select rectangular regions. When you select a structure or

object, the selection is displayed with a light blue frame around it with three types of

selection handles:-

A) Drag this handle to rotate the object.

B) Drag any corner to resize.

C) Drag any side handle to distort.



The Lasso Tool

Use the Lasso tool to make freehand selection of irregular areas. To select objects using

the Lasso tool:

1. Select the Lasso tool.

2. Press the mouse button while the pointer is not over any object.

3. Drag around part of a structure or other object.

The Marquee Tool

Use the Marquee tool to select objects and structures within a rectangular area.

1. Select the Marquee tool.

2. Click and drag diagonally over the structures or other object.

As you drag, a rectangle appears that defines the selection area. Bonds and other objects

are selected only if they are entirely within the rectangle.

Selecting entire structures

To select an entire chemical structure, double-click a bond or atom in the structure

using a selection tool.

Character Map

The floating Character Map window displays the 256 characters in any font. The

default font is Symbol. Use it to add symbols or styled fonts to labels. The character map is

active only when a text box is open for editing.

With a text box open, mouse over the character map to view a larger version of the

characters in the top right corner of the window.

Click any character in the table to enter that character in the text box.



Bonds

The Main toolbar and Multiple Bonds toolbar offer numerous options for drawing

bonds.

To draw the first bond of your structure, select the solid bond tool in the Main toolbar

and click in the document window.

To draw another bond, point to an atom where a grey box appears then click.

You can draw a bond in any direction. Using a bond tool, click and drag from an

existing atom or an empty area in the document window.



There are several ways to draw a double bond:

Draw a bond using the Double bond tool.

Draw a single bond over an existing single bond.

Using any bond or selection tool, point to an existing bond and type ‘2’

To draw triple or quadruple bonds:

Draw a bond using the triple or quadruple bond tool.

Using any bond or selection tool, point to an existing bond and type‘3’ or ‘4’.

Changing the Bond Order

You can reduce or increase the order of bonds in a structure by using the Bond

Properties dialog box or with the shortcut menus as follows.

To reduce the bond order:

1. Point to the bond to change and Right-click or Control-click.

2. Choose the appropriate bond type from the shortcut menu that appears.

To use the eraser tool for reducuing the bond order:

1. Click the Eraser tool.

2. Click a single, double, or triple bond. The bond order is reduced by one.

Bond Hotkeys

To modify a bond, place your mouse over the bond and select a key (K) listed below:



Function K Function K

Change to single bond 1 Change to bold bond b

Change to double bond 2 Change to dashed bond d

Change to triple bond 3 Change to hashed bond H

Change to quadruple bond 4 Change to hashed-wedged bond h

Center a double bond c Change to wedged bond w

Double bond to the left l Change to wavy bond y

Double bond to the right r Open a bond properties text box / or ?

Rings

You can draw aliphatic and aromatic rings of different sizes and types.

1. In the Main toolbar, select a ring tool.

2. Click and drag in the document window to orient the ring.

If you click an atom or bond with a ring tool in an existing structure, the ring is fused

to it.

Spiro and sprout rings

By default, clicking an atom in a ring using a ring tool forms a spiro link.



You can change this behavior so that a sprout bond appears instead:

1. Go to File>Preferences.

2. On the Building/Display tab, check the box next to Sprout Rings Instead of Spiro

When Clicking.

Aromatic Structures

Delocalized rings: You can draw a resonance delocalized ring using any ring tool except for

the cyclohexane chairs.

1. Click a ring tool.

2. Press the Ctrl key and click in the document window.

Resonance structures: You can draw benzene in either of their two orientations:

1. Click a ring tool.

2. Press the Shift key and click in the document window.

Adding chains to structures

To add an acyclic chain to an existing structure, click an atom in the structure. Click

and drag in the direction you want to draw the chain.

Specifying chain length: To specify the exact length of a chain before drawing:

1. Select the Acyclic Chain tool.

2. Click an existing atom or an empty area in a document window. The attach Chain

dialog box appears type the numbers of atoms in the chain then click Attach.

3. Or click and drag in the document window in the direction you want the chain to

grow. The number at the end of the chain indicates how many atoms you have drawn.



Changing Chain Direction

To change the direction of the chain as you draw: Press Ctrl key while drawing

chains in the direction you want.

Moving Atoms

You can use any of the bond tools to move an atom within acyclic or cyclic structures.

You cannot use a ring tool.

To move an atom in a chemical structure:

1. Click a bond tool.

2. Point at the atom to move. A highlight box appears over the atom.

You can convert ring types by dragging one atom on top of an adjacent atom, e.g. if

you want to convert a 6-membered ring into a 5-membered ring perform the following:-

1. With a bond tool selected, point to an atom and Shift+Drag.

2. Release when one atom is on top of the other, the bond between the atoms

disappears.



Captions and Atom labels

Chem Draw enables you to create the following types of text:

Caption text: - Create annotations, chemical names, chemical formulas, page titles,

and information in tables.

Atom label text: - Identify atoms and substructures by their chemical symbols and

formulas.

Tutorial: Drawing a chemical structure of Aspirin (acetylsalicylic acid):

To add the carboxylic moiety:

Select the Text tool, click the end carbon on the methyl group, a text box appears.

In the text box, type COOH, then click the entr key or click outside the text box.

To add the caption Aspirin: Acetylsalicylic acid:

Select the Text tool, click below the drawing and type “Aspirin: Acetylsalicylic acid”

in the text box.

Click outside the text box.

(To edit the caption or atom label, click in the text box with the text tool and begin

typing).

Shortcuts and Hotkeys

Hotkeys are organized into atom labels, bond types, and functions such as adding a

charge or displaying a bond.



Atom Keys

Using Hotkeys, you can add functional groups to your structures with one keystroke.

For example, place your mouse over an atom and press ‘1’ (to add n-butyl group), ‘2’ (sec-

butyl group), ‘3’ (ter.-butyl group), ‘4’ (phenyl), b (Bromine) c (Carbone), e (ethyl), f

(fluorine), i (iodine), l or C (Chloride), n (nitrogen), N (sodium), O (oxygen), s (sulfur), and

…..

Deleting structures, bonds or atoms:

To delete the entire structure, do one of the following:

Select the Eraser tool, double click on any atom or bond in the structure.

Select the entire structure with the Marquee or Lasso tool and press Backspace

or Delete.

To remove any bond or atom, do one of the following:

Click the bond or atom with the Eraser tool.

Point to the bond or atom with the Marquee or Lasso tool and press Backspace

or Delete.

Atom Numbering

You can add sequential numbering indicators to atoms. The types of indicators are

(The default indicator is numbers):

Numbers (1, 2, 3, and so on)

Text ending with a number (atom1)

Greek letters in the Symbol font

Letters (a, b, c, and so on)

Showing Atom Numbers

1. Select one or more atoms to number.

2. While pointing to the selected atoms or structure, do one of the following:

Right-click, point to Atom on the context menu, and click Show Atom

Number.

Type the HotKey ‘ (single quote).



Hiding atom numbers

1. Select the atoms or structure.

2. Right-click, point to Atom, and deselect Show Atom Number.

To remove an atom number indicator, do one of the following:

Click the indicator with the Eraser tool.

Point to the indicator with the Marquee or Lasso tool and press Backspace or

Delete.

Editing Atom Numbers

To edit the atom number text and style:

1. Select the Text tool.

2. Select the atom number indicator and type the changes.

3. To edit the atom number style, select the atom number indicator with the Text tool

and use the Text menu or Text formatting toolbar.

The Chemical Symbols Tools Palette

Use the Chemical Symbols tools to add chemical symbols to your structure. When you

click the Chemical Symbols tool, the following palette appears:



When you attach a symbol (other than H-dot or H-dash) to an atom, it remains at a

fixed distance from the central character of the atom label. If you drag the symbol, it will

maintain that fixed distance as it moves around the atom.

Lone Pair Symbol

It is used to indicate a lone pair of electrons common in Lewis structure

representations. To draw a lone pair:

1. Hold down the mouse button over the Chemical Symbols tool and drag to select the

lone pair from the palette.

2. Point to the atom where you want the lone pair located and drag in the suitable

direction to position it then release.

Radical, Radical Cation and Radical Anion

Radical symbol is used indicate a single non-bonded electron.

Radical cation and radical anion symbols are used to represent radicals that are

charged.

To draw a radical, radical cation or radical anion symbol:

1. Hold down the mouse button over the Chemical Symbols tool and drag to select the

symbol from the palette.

2. Point to the atom where you want the symbol to appear then Drag from the charge

portion of the symbol to the radical portion of the symbol.



Charge Symbols

Charges are always assigned to a specific element in the atom label, whose acceptable

valences become those of the similar isoelectronic neutral element.

To draw a charge and associate it with a structure:

1. Hold down the mouse button over the Chemical Symbols tool and drag to select

the charge symbol from the palette.

2. Click to the atom to which you want the charge to correspond.

The number of hydrogen atoms increases or decreases as appropriate for the addition

of the charge.

Using hotkeys to draw a charge and associate it with a structure:

1. Select the atom to which you want the charge to correspond.

2. Press the key board bottom "-" to add a negative charge or "+" to add positive

charge.

Rotating a Symbol

All symbols are rotated around the same end from which they were originally drawn

To rotate a chemical symbol:

1. Select the chemical symbol with a selection tool.

2. Drag the Rotation handle on the chemical symbol.

Coloring Text or Structure:

You can color captions, atom labels and structure as a whole or in part by select the

captions, atom labels and structure by the lasso tool then:.



1. From the Color menu, choose a color.

2. Or right clink then selecting the color from the menu and choose a color.

3. Or selecting the color tool from style toolbar

Rotating Objects

1. Select an object to rotate. The Rotation handle is at the top of the selection rectangle.

2. Drag the Rotation handle clockwise or counterclockwise.

To rotate a selected object by a specified angle:

1. Select an object to rotate, right click over the object, select rotate from the menu.

2. The Rotate Objects dialog box appears, enter a number and click either degrees CW for

a clockwise rotation or degrees CCW for counterclockwise rotation [(Optional) to rotate

the atom label text, select Rotate Atom Labels].

3. Click Rotate. Objects are rotated around the center of the selection rectangle.



Moving Objects

To move an object:

1. Select the object using a selection tool.

2. Point within the border of the Selection rectangle.

3. Click and drag the object.

To constrain the movement to the horizontal or vertical direction: Shift+drag the

selected objects.

Copying Objects

1. Select one or more objects.

2. Ctrl+drag or Option+drag the object(s) to create a copy and position it.

To constrain the copy to move only vertically or horizontally while positioning it, hold

down the Shift+Ctrl or Shift+Option keys.

Deleting Labels

To delete an atom label, leaving the underlying bonds unchanged, do one of the

following:



Select the Eraser tool and click the atom label.

With a selection, bond, or ring tool selected, point to the atom label and press the

space bar, Backspace, or Delete key.

Deleting Objects

To delete selected objects, do one of the following:

Press the Delete key.

Go to Edit>Clear.

Also you can delete the whole structure through selecting the Eraser and double

clicking on any part of the structure.

Drawing Arrows and Shapes

Use the tools and tool palettes on the main toolbar to add shapes to your documents.

Overview: Chem Draw provides four tools that enable you to add shapes to your

documents:

Orbital tools palette Draw orbitals

Chemical Symbols tools

palette

Draw charges, radicals, and other

symbols.

Arrow tools palette Draw arrows.

Drawing Elements tools

palette Draw boxes, circles, and lines

Brackets tools palette

Draw brackets, braces, parentheses,

and daggers.

Arc tools palette draw arcs

Pen tool Draw freehand shapes.

Selecting Tools from the Palette

The Arrow, Arc, and Drawing Elements tools each contain a palette with different

types of that tool.



When you choose a tool type from the palette, it becomes the default. To use a

different tool type, select it.

To select a tool and use its default tool type Click the tool’s icon to select it.

To choose a different tool type from the palette:

1. Point to the tool’s icon and hold down the mouse button. The palette appears.

2. Drag to select a tool type from the palette.

3. Release the mouse button over the object you want to select.

Framing Objects

You can enclose your drawings or group structures with a rectangle, brackets,

parentheses, or braces. To enclose your object:

1. Select one of the box tools.

2. Point where you want a corner of the box to be located.

3. Drag from one corner of the box diagonally to the opposite corner.

Also you can enclose your object by another method:

1. Select the drawing to enclose.

2. Right click, Add Frame and select the frame type.



Drawing Circles and Ovals

To draw a circle or oval:

1. Select one of the circle or oval tools.

2. Point where you want the center of the circle to be located.

3. Drag outward from the center.

Drawing Paired Brackets

Paired brackets can only be placed in a vertical orientation. A rectangle or box defines

their position. To draw paired brackets:

1. Select a paired bracket tool.

2. Point where you want a corner of the bracket to be located.

3. Drag from one corner of the box diagonally to the opposite corner.

Note: while selecting the bracket tool, double clickin on the bracket will change its direction.

Arrows:

There are many arrows types available (e.g. such as crossed (no-go) arrows,

equilibrium arrows of unequal lengths, and elliptical arcs.), letting you add a wide variety of

reactions and annotations to your drawings.



You can customize arrows not only for length and angle, but for arrowhead width and

shape. You can also drag an arrow from its middle to create an arc of any length.

When you mouse-over an arrow with the Lasso, Marquee, or an Arrow tool selected,

the application switches to edit mode and adjustment handles appear on the arrow.

Arrows are used do outline diferent metabolic and synthetic pathways.

While selecting the arrow, double cliking on the arrow will revese its direction.

Working with Structures

1- Automatic Error Checking (Checking Chemistry)

Chem Draw automatically checks for correct chemical syntax as you draw. If Chem

Draw finds an error, a red box is displayed around the erroneous object. The red box

is display only and does not print.

To view a description of the error, do one of the following:

o Right-click on the error and choose Explain This Warning.



To check the valences of all selected atoms in a structure:

1. Select a structure, part of a structure, or caption with a selection tool.

2. From the Structure menu, choose Check Structure.

Each label in the structure is checked, sequentially. When a label is incorrect, a

message window appears.

To continue checking the structure when a message appears:

Click Ignore: - To ignore all subsequent errors in a structure:

Click Ignore All: To stop checking a structure when a message appears:

Click Stop:-The check ends and the atom that is causing the problem are selected.

To disable the automatic error checking:

o On the Tools menu, deselect Show Chemical Warnings.

This setting applies to all documents.

To disable the automatic error checking on a specific object:

o Right-click the object and choose Display Warnings.

When Display Warnings is deselected for an object:

o Red boxes are not displayed for errors.



o Errors are not reported by the Analyze Structure or Check Structure commands.

2- Structure Clean Up

The Structure Clean Up command is used to neaten the appearance of molecules by

regularizing bond lengths and angles. Graphic objects such as arrows and aromatic circles

are not affected. Use Structure CleanUp to redraw structures that you may have drawn

freehand or to neaten structures that you may have imported from another application.

Structure CleanUp may not create the best structure.

To clean up the structure:

Select the structure and from the Structure menu, choose Clean up Structure.

3- Viewing Analysis Information

The Analysis window displays the chemical formula, exact mass, molecular weight,

m/e, and elemental analysis for the entire document, a structure, part of a structure, or

a caption in Formula style.

To view information about a selected structure:

1. Select structure.

2. From the View menu, choose Show analysis window, the Analysis window

appears.

To paste information about a structure as a caption:

1. Click the check boxes for the information that you want to paste.

2. Click Paste.

Formula: The molecular formula showing the exact number of atoms of each element in the

molecule and charges, radicals, and isotopes.



Exact Mass: The exact molecular mass of the structure, where atomic masses of each atom

are based on the most common isotope for the element.

Molecular Weight: The average molecular mass of the structure, where atomic masses are

based on the natural abundance of all isotopes of the element.

Elemental Analysis: The percent by weight of each element in the structure.

m/e: Mass/charge, where charge =1. The weights of the most common isotopes and a

graphical representation of the isotopic abundance is shown.

4- Viewing Chemical properties

To view information about the chemical properties of selected structure:

1. Select an entire structure, part of a structure, or a caption (in Formula style).

2. From the View menu, choose Show chemical properties window.

To paste information about a structure as a caption:



1. Click the check boxes for the information that you want to paste.

2. Click Paste.

5- Viewing the Stereochemistry:

When the Show Stereochemistry option is selected, Chem Draw calculates the absolute

stereochemistry for tetrahedral atoms and double bonds according to the Cahn-Ingold-

Prelog (CIP) priority rules.

Chem Draw calculates and displays the following stereochemical terms:

(R), (S)-Standard tetrahedral stereochemistry

(E), (Z)-Standard double-bond stereochemistry.

To show the stereochemistry of a structure:

1. Select an entire structure.

2. From the Object menu, choose Show Steriochemistry.



6- Drawing-Structures from Chemical Names

One of the most significant and useful features in Chem Draw is Struct=Name. Draw

or open a chemically correct structure and Chem Draw displays the IUPAC name.

In Chem Draw only, you can draw a structure automatically from a chemical name, by

using the Convert Name to Structure feature.

Chem Draw recognizes most organic nomenclature.

Most inorganic chemistry is recognized, especially when the rules closely match

those for organic chemistry.

Converting Names to Structures

Inserting Names: For example, to insert Acetyl salicylic acid:

1. From the Chem Draw Structure menu, choose Convert Name to Structure. The

Insert Structure dialog box appears.

2. Type Acetyl salicylc acid.

3. Click OK.

The molecular structure and name appear in the drawing area.

Converting Structures to Names

1. Select the chemical strucure

2. From the Chem Draw Structure menu, choose Convert Structure to Name.



NMR- prediction

Chem draw has the ability to predict proton and carbon-13 NMR, i.e. Chem NMR estimates

and displays proton and carbon-13 chemical shifts in ppm for a selected molecule.

To view 1H or

13C NMR information:

1. Select the target chemical structure.

2. From the Structure menu, choose 1H-NMR Shifts or

13C-NMR Shifts.

Chem NMR redraws the molecule with the estimated shifts and displays the

information and line spectrum in a new window.



Drawing with Templates

Template documents are collections of structures organized by structural type or

functionality.

A structure in a Template document is named a template. Use an existing template

instead of drawing the structure to shorten the time required to create documents.

The Templates Tool:

The Templates tool contains a palette from which you can select different types of

structures or objects. The Templates tool has two levels:

o The first level displays the available Template documents.



o The second level displays the templates within each Template document.

Drawing a Template

To draw a template: Click in a document window. The template is drawn centered

around the pointer in the orientation that it appears in the Templates palette.

Fusing a Template with an Existing Structure

To draw a template and fuse it with an existing structure:

Click an existing bond in a document window.

To deposit a template and create a spiro-linkage with an existing structure:

Guided by the Chem Draw program, draw the following structures



Guided by the Chem Draw program, draw the following pathways:



PART 2

Physicochemical Properties of Drug Action

Acid/base properties

Different types of functional groups commonly exist in drugs are listed in the following

tables:



Identify the functional groups of each of the following drugs and determine whether they

are acidic, basic and/or neutral.

Answer:

For aspirin:

For fluoxetine:

For chloropromazine:



For amlodipine:

For fexofenadine:

For ciprofloxacin:



Predicting the degree of ionization of drug molecule

1. Calculate the percentage of ionization of amobarbital (its pKa: 8.0) in the stomach (pH ~

2.0), duodenum (pH ~ 5.5), and ileum (pH ~ 8.0). Discuss the effect of pH on its

ionization.

Answer

In the stomach (pH ~ 2.0):

pH = pKa + log([A-]/[HA])

2 = 8 + log([A-]/[HA])

-6 = log([A-]/[HA])

[A-]/[HA] = 0.000001

As shown above, (pH ~ 2.0) amobarbital is in the unionized form (~100%)

In the duodenum (pH ~ 5.5):

In the ileum (pH ~ 8.0):

Comment:



2. Calculate the percentage of ionization of phenylpropanolamine (its pKa: 9.4) in the

stomach (pH ~ 2.0), duodenum (pH ~ 5.5), and ileum (pH ~ 8.0). Compare these results

with those obtained with amobarbital.



3. Calculate the percentage of ionization of sulfacetamide in the stomach (pH ~ 2.0),

duodenum (pH ~ 5.5), and ileum (pH ~ 8.0). Draw the structure of the predominate form

of the drug in each site.

Sulfacetamide has the following structure and pKa values:

Answer:

In the stomach:

In the duodenum:

In the ileum:



4. For the following organic functional groups, name each one, and show all possible

hydrogen bonds with water.

Answer:



Hydrophilic/lipophilic properties

(Water and lipid solubility)

Guided by the following table which represents water-solubilizing potential of organic

functional groups in a polyfunctional molecule, predict the water solubility for each of these

compounds using the empiric method of Lemke:

Functional Group Monofunctional

Molecule Polyfuncational

Molecule

Alchohol 5-6 Carbons 3-4 carbons

phenol 6-7 Carbons 3-4 Carbons

Ether 4-5 Carbons 2 Carbons

Aldehyde 4-5 Carbons 2 Carbons

Ketone 5-6 Carbons 2 Carbons

Amine 6-7 Carbons 3 Carbons

Carboxylic acid 5-6 Carbons 3 Carbons

Ester 6 Carbons 3 Carbons

Amide 6 Carbons 2-3 Carbons

Urea, carbonate,

carbamate

2 Carbons

N.B:

Each charge on a molecule, anionic or cationic contributes to the solubility of 20-30

carbons.

1-Aspirin:

Funtional Group Value

1 Carboxlic acid 3 Total 6

1 Ester 3 Number of carbon atoms 9

So the drug is water insoluble because the carbon solubilizing potential is

less than carbon number.



2-Betaxolol

3-

4-

Funtional Group Value

1 Amine 3 Total 10-11

1 Alcohol 3-4 Number of carbon atoms 18

2 Ether 4

So the drug is water insoluble because the carbon solubilizing potential is

less than carbon number.



5-

6-



7-

8-



The hydrophobicity constant (π)

Hansch constant

Guided by the following table that represents hydrophilic/lipophilic values of different

atoms and functional groups. Calculate logP value for each of the following compounds:

1-Aspirin:

Fragment π value Fragment π value

1 Carboxylic acid -0.7 1 Aliphatic Carbons +0.5

1 Ester -0.7 LogP +1.1

1 Phenyl +2.0



2-

3-

4-



5-

6-

7-



8-

9-



Case Study

Case 1

Each of these drug molecules interacts with different biological targets and elicits a unique

pharmacologic response. For each of these molecules, point out and name the sites of

different types of non-covalent bonding that could be formed with the target receptor.



Case 2

When you look at any drug molecule, there are a number of functional groups that

contribute to the properties of that drug molecule. Analyze the following structures and

assign the different hydrophilic and lipophilic parts in the structure.



Case 3

A long-distance truck driver comes into the pharmacy complaining of seasonal allergies. He

asks you to recommend an agent that will act as an antihistamine but that will not cause

drowsiness. He regularly takes an antacid for indigestion because of the bad food that he

eats while on the road.

1. a) Calculate log P value of each drug guided by the previous table that represents

hydrophilic/lipophilic values of different atoms and functional groups?

b) Based on your answers, provide a rational for whether the truck driver should be

taking cetrizine or clemastine?



2. The pKa value of cetrizine is 2.9 and its % ionization is 11.2% in the stomach (pH ~

2). The antacid neutralizes stomach acid to pH = 3.5. Determine whether the truck driver

will get the full antihistaminergic effect if he takes his antihistamine with the antacid at the

same time. Provide a rational for your answer?



Case 4

The nurse in the hospital pharmacy gets an order for a patient that includes the two drugs

drawn below. She is unsure if she can mix the two drugs together in the same IV bag and is

not certain how water soluble the agents are.

1. What is the chemical consequence of mixing aqueous solutions of each drug in the

same IV bag? Provide a rationale that includes an acid base assessment?



Case 5

A 24-year-old man comes into the pharmacy and asks you to recommend a treatment for the

itching and burning he has recently noticed on both feet. He indicates that he would prefer a

cream rather than a spray or a powder. Your recommendation to this patient is to use

terbinafine, a very effective topical antifungal agent that is sold over-the-counter.

1. Identify the structural characteristics and the corresponding properties that make

terbinafine an agent that can be utilized topically?

2. The biological target of drug action for terbinafine is squalene epoxidase. Consider

each of the structural features of this antifungal agent, and describe the type of interactions

that the drug will have with the target for drug action. Which amino acids are likely to be

present in the active site of this enzyme?



Case 6

A mother presents a prescription for her 6-month-old daughter for pediatric drops that

contains:

Phenylephrine (decongestant)

Chlorpheniramine (antihistamine)

Guaifenesin (expectorant)

She wants to know if this medication will have an effect on her daughter's alertness.

1. Identify the structural features/functional groups of phenylephrine and guaifenesin

that contribute to improved water solubility (medication given as drops). List the type(s) of

interactions that these groups have with water, and draw an example of these interactions

(with appropriate labels) below.



2. a) Determine the functional groups that will allow the drug to cross the blood-brain

barrier (have an effect on this child's alertness)?

b) Calculate log P value for each drug (guided by the previous table that represents

hydrophilic/lipophilic values of different atoms and functional groups)? Determine which

agent is likely to have the most significant effect on the alertness?

3. Identify the binding interactions that chlorpheniramine and guaifenesin could have

with their respective targets for drug action?



PART 3 Case study "Antifungal drugs"

Case 1 MJ is a 67-year-old male heart transplantation patient receiving immunosuppressive

therapy (cyclosporine and corticosteroids) who was readmitted to the hospital 2 months

after his surgery, complaining of fever, malaise, joint pain and painful oral lesions (white

plaques). Cardiac output and renal function tests were normal, indicating that there were no

signs of tissue rejection. A chest radiograph revealed diffuse lung infiltrates. Blood and

throat cultures yielded Candida albicans. Therapy was initiated for MJ with amphotericin B

by slow IV infusion. After 20 hours, severe thombophlebitis developed near the injection

site. Although miconazole (4) is available for IV administration, the cardiologist was

reluctant to use it.

Structure (1) Structure (2)




Question 1:

Describe the injectable form of miconazole (4). What is the basis for the physician’s

reluctance to administer it to this patient?

The correct answer is:

Question 2:

Select, from the imidazole antifungal structures (1-3) given, the most appropriate one

for IV administration to this patient. Justify your choice based on structure/solubility

properties.




Case 2

W.U is 5 years old, she complained from skin infection. Her mother took her to

dermatologist. She told him that infection started week ago. The doctor diagnosed her taenia

pedis.



Question 1:

Identify and comment on mode of action for different drugs.




Question 2:

Suggest one of the provided drugs which could be used as drug of choice and which of

them could be used orally for treatment of topical infection?


Question 3:

Select, from the imidazole antifungal structures (1-3) given, the most appropriate one

for IV administration to this patient. Justify your choice based on structure/solubility

properties.




PART 4

Titrimetric Determination of Pharmaceutical Preparations

Penicillins

Benzylpenicillin

Principle: (iodimetric assay)

Benzylpenicillin doesn’t react with iodine in neutral aqueous medium. In alkaline

medium, the alkaline penicillin is decomposed giving penicilloic acid which can be oxidized

by known excess standard iodine and the excess unused is back titrated against standard

sodium thiosulfate using starch as indicator.

Procedure:

Reconstitute one vial of benzylpenicillin with water, transfer the solution into 200

mL measuring flask, wash the bottle three times with water, transfer the washing

into the measuring flask and complete to the mark with water.

Transfer 5.0 mL into glass stoppered conical flask, add 5.0 mL 1.0 M NaOH and

stand for 30 minutes over a boiling water bath.

Cool, and then add 7.0 mL 1.0 M HCl followed by 25.0 mL 0.02 M iodine.

Allow to stand for 15 minutes then titrate the excess iodine against 0.02 M sodium

thiosulfate (Na2S2O3) using starch as indicator (starch is added when solution color

becomes straw yellow).



Laboratory Report

Results and calculations for ….………………………………… Group: ……………….………

Student Name: ……………………………….………………………………… Student No.:- ………………

Results and calculations:-

2 2 4

4 Moles iodine = 1 mole benzylpenicillin

1iodine = Benzylpenicillin

4

E.P = mL M Na S O

M.wt of benzylpenicillin x Molar ratio Molarity1 mL M iodine

1000

1Mole of iodine

2 2 4 = 2 mole Na S O

x Ep 100%Purity (25- factor Dilution factor

2 weight of vial)



Cephalosporines

Cephalexin

Principle:

Cephalexin doesn’t react with iodine in neutral aqueous medium. In alkaline medium,

the alkaline decomposition product can be oxidized by known excess standard iodine and

the excess unused iodine is back titrated against standard Na2S2O3 starch as indicator.

Cephalexin Oral Suspension (Ceporex 250 mg)

Procedure:

Reconstitute the powder of the oral suspension with water to the mark of the bottle

(60.0 mL), transfer 5.0 mL into 250 mL measuring flask and dilute to mark with water.

Transfer 5.0 mL into glass stoppered conical flask; add 5.0 mL 1.0 M NaOH then

stand for 20 minutes.

Add 20.0 mL acetate buffer solution (to adjust pH at 4.6), 5.0 mL 1.0 M HCl followed

by 25.0 mL 0.01 M iodine and stand for 20 minutes.

Titrate the excess unused iodine against 0.02 M Na2S2O3 using starch as indicator

(starch is added when solution color becomes straw yellow).



Laboratory Report




2 2 3

2

4 moles iodine 1 mole cephalexin

E.P = mL M Na S O

M.wt of cephalexin Molar ratio x Molarity of iodine1 mL M iodine

1000

1 mole iodine 2 mole Na S

2 3O

x Ep 100% Purity (25- Factor Diltution factor

2 weight taken

)



Sulfonamides

Group I : Acidic NH which can be assayed argentometrically

Group II : Primary aromatic amino group can be assayed diazometrically,

bromometrically (direct or indirect)

1- Principle of Argentometric assay:

Sulfonamides have acidic properties as they contain acidic hydrogen thus react with

excess standard silver nitrate with the precipitation of silver salt and release of nitric acid.

The excess unused silver nitrate can be back titrated against ammonium thiocyanate

using ferric alum as indicator (Volhard method) or the released nitric acid can be titrated

against NaOH (acid-base titration).

(Excess unused)

Or

2- Principle of Indirect Bromometric Assay:

Sulfonamides react with excess standard bromine solution giving dibromo derivatives.

The excess unused bromine was reacted with potassium iodide to give equivalent amount of

iodine which can be titrated against sodium thiosulphate solution using starch as indicator.

Sodium tetrathionate



3- Principle of Direct Bromometry:

It depends on direct titration of the sample with standard potassium bromate (KBrO3)

solution in the presence of potassium bromide in acidic medium (Conc. HCl).

In acidic medium, KBrO3 oxidize bromide into bromine which reacts with

sulfonamides and at the end point the first excess of bromine oxidize the indicator (methyl

red or methyl orange).

4- Principle of Diazometric Assay:

The free basic amino group in sulfonamides can be diazotized with nitrous acid

produced in situ using mixture of NaNO2/HCl to give the corresponding diazonium salt. The

end point can be detected using either external indicator such as potassium iodide starch

paper or internal indicator such as metanil yellow.

Notes:

This titration must be carried out in ice bath to achieve stability of nitrous acid.

The tip of the burette must be kept under the surface of the solution to prevent escaping

of nitrous acid.



Determination of ZnSO4/Sulfacetamide sodium

A- Sulfacetamide sodium (Molecular weight of sulphacetamide sodium = 254)

Procedure:

Transfer 10.0 mL sample into a glass conical stoppered flask, add 25.0 mL 0.05 M

Br2 and 2.0 mL Conc. HCl.

Stand for 15 minutes then add 10.0 mL 10% potassium iodide solution.

Titrate the liberated iodine against 0.05 M Na2S2O3 using 1 mL starch as indicator.

B- Zinc Sulfate (Molecular weight of ZnSO4.7H2O = 287)

Procedure:

Transfer 10.0 mL sample solution to a glass conical flask, add 10.0 mL distilled

water and 2.0 mL ammonia buffer solution (pH = 10.0)

Titrate against 0.05 M EDTA (Ethylene Diamine Tetraacetic Acid) using few

specks of Eurochrome Black T (E.B.T.) indicator



Laboratory Report



A- Sulfacetamide sodium


2

2

2 2 3

2

2 moles Br 1 mole sulfacetamide sodium

1 Br sulfacetamide sodium

2

E.P.= mL Na S O

M.wt of sulfacetamide sodium Molar ratio x Molarity 1 mL 0.05 M Br

1000

2 2 2 2 3

2 2 3 2

1mole Br 1mole I 2 moles Na S O

1Na S O Br

2

x Ep 100Concentration (25- ) factor

2 volume taken



Laboratory Report



B- Zinc Sulfate




Assay of zinc undecenoate

Product formula C22H38O4Zn Molecular weight 431.9

Action and use

Zinc undecenoate is used topically in treatment of fungal infections.

Zinc undecylenate is an antifungal agent with uses similar to those of

undecenoic acid. It is used to treat or prevent athlete’s foot. It usually used in

combination with undecenoic acid to kill the fungus and the germs that lead to the

symptoms of athlete’s foot.

Definition: Zinc di(undec-10-enoate).

Content: Zinc undecylenate contains not less than 98.0 per cent and not more than

the equivalent of 102.0 percent of zinc di(undec-10-enoate), calculated with reference

to the dried substance.

Solubility: Practically insoluble in water and in ethanol (96 per cent).

Assay: Carry out the complexometric titration of zinc.

Procedure:

Transfer 10.0 mL sample to a glass conical flask, add 10.0 mL distilled water

and 2.0 mL ammonia buffer solution (pH 10.0).

Titrate the mixture against 0.01 M EDTA solution using few specks of

Eurochrome Black T (E.B.T.) indicator till pure blue color was obtained.



Laboratory Report



Calculation:

1 mole EDTA 1 mole Zinc undecenoate

M.wt of Zinc undecenoate x Molar ratio x Molarity 1 mL M EDTA =

1000

= g Zinc undecenoate

E.P = mL

EDTA

100 % Conc. = EP x Factor x

Volume taken

= g %



Propylparaben

Used as preservative.

Principle:

It depends on hydrolysis of the ester using known excess of standard alkali and the

excess unused alkali is back titrated against standard acid using phenolphthalein indicator.

NaOH+ HCl NaCl + H2O

Procedure:

In a beaker, 0.5 g propylparaben powder is heated with 25.0 mL 1.0 M NaOH over a

boiling water bath for 30 minutes.

Transfer the contents of the backer into a 100 mL measuring flask, wash the beaker with

few mL of water and transfer the washing to the measuring flask and complete to the

mark with water.

Transfer 10.0 mL of the solution into a conical flask, add 10 drops of phenolphthalein,

and titrate against 0.2 M HCl.



Laboratory Report






Betadine

(Povidone iodine)

2-Pyrrolidinone-1-ethenyl polymer compound iodide

It’s a complex of iodide with povidone. It is used as antiseptic solution and used pre-

operation to prevent wound infection.

Advantages: Non-staining and non-irritant.

Principle:

a) Determination of total iodide:

By adding drops of sodium bisulfite (NaHSO3) till the brown color of the iodine

disappears where iodine is converted into iodide.

Then the total iodide is treated with known excess standard AgNO3 and the excess

unused AgNO3 is back titrated against standard NH4SCN using ferric alum as

indicator.

b) Determination of available iodine:

Stirring of betadine sample for 1 hour then titrated against standard Na2S2O3 using

starch as indicator.

Total I2-available iodine = iodide in the complex (officially not more than 6.6%)

Determination of available iodine in betadine sample:

Procedure:

Transfer 10.0 mL betadine sample into glass stoppered conical flask, add 10.0 mL water

and titrate against 0.05 M Na2S2O3 using 1.0 mL starch as indicator.



Laboratory Report






Isoniazide (INH)

It is used for treatment of tuberculosis

Principle: (Indirect Bromometry)

Oxidation of INH with known excess standard Br2 will give isonicotinic acid and the

excess unused Br2 can be determined by adding 10% KI to liberate equivalent amount of

iodine which can titrated against standard Na2S2O3 using starch as indicator.

Excess unused

Procedure:

Transfer 10.0 mL of the sample into glass stoppered conical flask, add 25.0 mL

0.05 M Br2 and 2 mL conc. HCl.

Stand for 15 minutes then add 10.0 mL 10% KI solution.

Titrate the liberated iodine against 0.05 M Na2S2O3 using 1.0 mL starch as

indicator.



Laboratory Report






Busulphan

(Anticancer alkylating agent)

1,4-Butanediol dimethanesulfonate ester

Principle:

Busulphan undergoes hydrolysis by heating with water to give two molecules of

methanesulfonic acid and one molecule of 1,4-butanediol. The produced methanesulfonic

acid is highly acidic and could be titrated against standard sodium hydroxide.

Procedure:

Transfer 10.0 mL busulphan sample into a glass conical flask; add 10.0 mL water

and warm gently for 5 minutes.

Cool and titrate against 0.1 M NaOH using 10 drops phenolphthalein indicator.



Laboratory Report




1 mole busulfan 2 mole methane sulfonic acid 2 mole NaOH

11 mole NaOH mole busulfan

2

M.wt of busulfan x Molar ratio x Molarity 1 mL M NaOH =

1000

= g bu

sulfan

E.P= mL NaOH

100 % Conc. = EP x Factor x

Volume taken

= g %



Problems

a. Calculate the number of grams of sulfacetamide sodium equivalent to 1.0 mL of 0.02 M

KBrO3. (M. wt. of sulfacetamide sodium = 254).

b. Calculate the number of mL of 0.1 M Br2 consumed by 10.0 mL of sulfacetamide

sodium sample (0.7 %). (M. wt. of sulfacetamide sodium = 254).

c. Calculate the number of grams of busulphan equivalent to 1.0 mL of 0.1 M H2SO4. (M.

wt. of busulfan= 246).



d. Calculate the number of mL of 0.01 M silver nitrate consumed in the assay of 10.0 mL

of sulfacetamide sodium (0.45%). (M. wt. of sulfacetamide sodium= 254).

e. In the determination of a sample of propylparaben powder, a weight of 0.5 g of the

powder was heated with 25.0 mL 1.0 M NaOH, then transferred to a 100.0 mL

measuring flask and completed to the mark with water. A volume of 10 mL of the latter

solution was titrated against 0.2 M HCl and 9.5 mL were consumed in the titration. What

is the %purity of propyl paraben powdered sample (M. wt. of propyl paraben= 180).



f. In the assay of cephalexin oral suspension (99% w/w purity), 5.0 mL equivalent to 250

mg cephalexin were hydrolyzed and determined iodimetrically. Calculate the number of

mL of 0.2 M iodine consumed in the assay. (M. wt. of cephalexin= 347).

g. In the determination of sulfacetamide sodium eye drops by the indirect bromometric

method, a volume of 10.0 mL of the eye drops was completed to 100.0 mL with water,

and 10.0 mL of the diluted solution were treated with 25.0 mL of 0.05 M Br2. If 8.0 mL

0.1 M Na2S2O3 was consumed, find the % concentration of the eye drops. (M. wt. of

sulfacetamide sodium= 254).

h. Calculate the number of mL of 0.5 M iodine consumed by penicilloic acid produced

after alkaline hydrolysis of 0.5 g of benzyl penicillin sodium (99 % w/w purity). (M. wt.

of benzyl penicillin sodium = 356).



Evaluation Sheet Student's name: ....................................................................................................................................

Student's number: ....................................................................................................................................

Lab Date Lesson Mark Signature

1

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