Subject:  Product Formulation/Mfg                          Date: December 2005

 

Subject Code: PFM714           Duration: Approx.3 Hours            Instructor:  V. Shulman         

                                               

INSTRUCTIONS AND INFORMATION

This Paper Is Due Before Midnight on Saturday December 10th 2005

 (Late penalty ¨C10% per day late)

 

Student Name:_________ ________________________

 

Student Number_____________

 

1.      This examination contains Ten (10) pages including this instruction page.  Please check now to ensure you have received a complete paper.

This paper has been sent as a word 2000 document. Please ¡°save as¡± using your name as the document extension!

 

2.      The grading scheme appears to the right at the end of each question.  Please gauge your time, length and detail of answer accordingly.

 

3.      Answer all questions. All answers are in your reference material or have been covered verbally in the classroom.

 

4.      Short answers (Bullet Points) are preferred. Marks will be awarded for clarity of answers.

 

5.       Please use this paper modified (if necessary) for your computer, to answer the questions.

 

6.       Answers to this exam are to be found in your notes or they were discussed during classes.

 

7.       This is a take home exam, however the answers and completion of this paper are to be done by the student alone ¨C any signs of plagiarism will result in BOTH or more parties will be penalized with no marks being allowed for the paper!!

 

3.Papers to be returned by E-mail to darvic@rogers.com 

 

Seneca Academic Policy on Cheating and Plagiarism (Section 8.8):

 

Cheating and plagiarism are offenses that will not be tolerated by the College. Such offenses occur when a student misrepresents his or her performance on any form of academic evaluation including, but not limited to, written assignments, lab experiments, group projects, tests or examinations. The penalty for a first offense of cheating or plagiarism is a grade "0" on the work in which the offense occurred. The penalty for the second offense of cheating or plagiarism is immediate expulsion from the college for the remainder of that semester or longer, depending on the circumstances.

                    

 

 

 

 

 

 

Email:

abnormalcrazy@yahoo.com

 

 

Question 1

List the three types of main processes used in the Pharmaceutical Industry

Give a very brief description of the process.

a)     Most difficult. Wet Granulation- The Mix is wetted, made into a granule, dried, resized, and finally remixed with additional lubricant and disintegrant

(Brief Description).                                               

b)     Next in degree of Difficulty. Dry Granulation- ¡®Sticks¡¯/wafers of chilsonate made by compaction using rollers are passed through a oscillator/mill to make granules

(Brief Description).

c)     Easiest. Direct compaction- materials are simply passed through a screen, and then blended without lubricant for 75% of the mixing time. (recirculate is necessary). Afterwards, lubricant is added, and eventually compressed

(Brief Description).

                                                                                                                                                (6)

Question 2

What 3 parts of the tablet press that control the flow of the granulation to the die?

a)     Hoppers

b)     Feed frames

c)     Scrapers

c) d)     The tablet press (turrent and cams/controls)                                                                                                                         (3)

 

Question 3

a) In your own words how are tablets compressed? 

___Granules are fed into feed frames by hoppers, and these feed frames uses paddles to force granulations into the dies. Scrapers then scrap off excess granules from the top of each die. Cams with pressure sensors and tracks for upper and lower punches to be filled and moved to a compression roller, thus creating a compressed tablet. _____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

 (5)

List the 7 stages of compression in detail, & state what part of the Tablet press is responsible for each stage of the compression process.

Compression stages

1.      __The cavity in the die is created by the lower punch pulled down by the fill cam . Fill cam size determines the depth of fill. ________________________________________________________________________________________________________________________________________________________________________________________________________________

2.      _Suction created by the punch moving downward, gravity, and/or paddles forcing granulation into the die (close feed frames) fills the die. _________________________________________________________________________________________________________________________________________________________________________________________________________________

3.      _The weight adjustment ramp/assembly and head corrects the volume of granulation into the die cavity. The spring loaded scraper then removes materials that escapes from the feed frame._________________________________________________________________________________________________________________________________________________________________________________________________________________

4.      _Height of the fill die is then moved below the die bore chamber by having the lower punch moving along the pull-down cam. _________________________________________________________________________________________________________________________________________________________________________________________________________________.

5.      _Precompression rollers expels air from between the granules and the die-making a soft tablet_________________________________________________________________________________________________________________________________________________________________________________________________________________

6.      ____the main compression rollers then compresses the granules into a tablet______________________________________________________________________________________________________________________________________________________________________________________________________________

7.       the ejection cam then pushes the punch tip to be 002¡± above the die table and the take off blade deflects the finished tablet down the discharge chute__________________________________________________________________________________________________________________________________________________________________________________________________________________                                                                                                                            (21)

                                                                                                                       

Question #4

Most Hard Gelatin Capsules can be made on automatic equipment using the active - plus 2 excipients / inactives, Name them and the function they play in the formulation.

1.      filler- fills excessive space in capsule

2.      glidant- allows materials to be more free flowing and not stick to machines/mixers..etc

(2)

Question #4a

In you own words; explain

1.      How Hard Gelatin Capsules are orientated and filled.

Empty capsules enter an orienting station(orienting blade and centrifugal force) from the hopper and aligned correctly into respective slots. Caps are then removed by vacuum suction. Powders are pushed into bodies by dosage holes/plungers. Caps are then replaces back onto their bodies, and eventually ejected by a set of upper and lower pings

 

 (8)

2.      List two (2) types of filling methods used on Semi Automatic or Automatic machinery.

1.auger

2.piston/doser filling or vacuum filling

 

(2)

 

Question #5

What colours would you suggest for use in capsules containing the following?

1.      Acetaminophen Caffeine & Codeine (Narcotic).

White/orange

2.      Flurazepam  (tranquilizer).

            blue/green                                                                                                                               (2)

Question #6

List the 5 stages in SUGAR COATING in order that they are applied

1.      sealing

2.      subcoating

3.      grossing

4.      addition of colour

5.      polishing

6.      Which of these steps could be combined? (Circle them) steps 2,3,4

7.      How is the sugar coating applied-made in conventional pans pouring liquid onto the product; or sprayed on.                                                                                                        (8)

                                                                                                                                               

Question #7

List the stages a drop of solution must go through to form a film during FILM COATING.

1.      ____formuation of a drop________________________________________________________________

2.      ____drop contacts the solid surface_________________________________(impingement)_______________________________

3.      ____drop spreads________________________________________________________________

4.      ____neighbouring drops coalesce______________________________________________(wetting and spreading)__________________

5.      ________________________________________________________________________additional drops form layers_____________________________________________

6.      ________________________________________________________________________A dry uniform film results after evaporation____(coalescence adhesion&autohesion)_

7.      How is film coating applied to tablets____________________________________________droplets are sprayed on, some penetrate core, and some coalesce and build up a film on the core. A film is created when sufficient solution is present._____________________

                                                                                                                                    (8)

Question #8

List four uses of a fluid bed dryer (other than simple drying). What is the most efficient way to use fluid bed equipment for granulating & drying?

1.      .granulating and drying

2.      .pellet coating

3.      .pellet manufacturing -spheronizing

4.      .high shear granulating- dense material

5.      .wurster coating

(4)

Question #9

List 5 reasons for coating tablets.

1.      .improve look

2.      .mask odour

3.      .increase ease of swallowing

4.      .easier to handle on high speed packaging lines                                                 

5.      .improved product stability

6.      .change drug release properties (delayed/enteric release)

                                                                                                                                                (5)

Question #10

List 4 properties required in a tablet core to allow for a good coating to be applied

1.      .it must not be too soft/friable

2.      .there should not be entrapped air to prevent laminating or capping

3.      .engraving cut should be open enough or prepicked to allow coating

4.      .it should have a correct shape (caplet vs modified caplet)

                                                                                                                                                (4)

 

Question #11

 

What are the 2 official methods for producing Water for Injection USP?

1.      .distillation

2.      .reverse osmosis

                                                                                                                                                (2)

 

Question #12

What 2 ingredients are required to be added during the production of Multi Dose Vials containing Adrenaline? (Sensitive to Oxygen) Give the functional name and list 2 specific examples of each.         -                                                                                                          

1.      ___ Anti-oxidants ---1.sodium metabisulphite_________________                    2.tartaric acid ____________________  __________________

2.      ___perservatives_________________    ________1.benzyl alcohol__2. parabenzoates__________      __________________

3.       sodium chloride+WFI = to balance ions                                                                                      (6)

Question #13

How do we preserve the Membrane in a Reverse Osmosis System and increase the amount of water produced?

Sediment filter and carbon filters first remove larger particles/chemicals

More pressure would be used to force water through the membrane

Membrane is configure to split feed water into 1.purified stream and 2. washed away stream that carry away rejected contaminants.

                                                                                                                                                 (2)

Question #14

How would you prepare Simple Syrup for production of large quantities of cough syrup?

            Syrup USP- sucrose is added to boiling water, stirred, filtered and color is added. API are added when syrup cools to lower temperature                                                                                                                             (3)

Question #15

List 4 thickening agents used in the manufacture of Syrups and Suspensions.

1.      .methyl cellulose

2.      .carboxymethylcellulose

3.      .guar gum

4.1.      .

4.      tragacanth

5.      xanthan, cellulose gums                                                                                                                                      (4)

Question #16

List 4 Sweetening agents (Natural)

1.      .liquid glucose

2.      .maltose

3.      .beet sugar           

4.      .     natural sucrose/sugar                                                                                                                         (4)                                                                                                                         

Question #17                                                                                                 

List 3 Sweetening Agents (Synthetic)

1.      .aspartame

2.      .asulfame potassium(nutrasweet)

3.      .saccharine                                                                                                                                               (3)

                                                                                                                                   

Question #18

List 4 popular flavoring agents with the appropriate colours to be used with them.

1.      .chocolate mint-brown

2.      .orange/ grapefruit- orange

3.      .grape- purple

4.      .  strawberry/cherry - red

                                                                                                                                                (4)

                                                                                                                                               

Question#19

Other than using Synthetic sweeteners, is there another type of syrup that could be used for Diabetics?

.          

sorbitol syrups- poorly absorbed from gut                                                                                                                                   (2)

                                                                                                                                   

 

Question #20

What part do the following play in this Syrup of Acetaminophen? (Some have more than one function)

Which ingredients solubilize the active ingredient?                                                                                                      (8)

ITEM #

INGREDIENT

PURPOSE IN SOLUTION

1

Acetaminophen

API

2

Alcohol 90%

Soluabilizing agent, preservative, sweetener

3

Glycerin

Solubilzer, sweetener

4

Propylene Glycol

Solubilzer, sweetener

5

Sucrose Granular

Preservative, sweetener, thickening

6

Liquid Glucose

Sweetener

7

Parahydroxy Benzoates

Preservatives

8

Acid Orange G Colour

Coloring

9

Tutti Frutti Essence

Flavor

10

Purified Water to

solubilizer

 

Question #21

Suggest a method of manufacture the syrup above on a large scale ¨C list some equipment to manufacture a 1000L batch. Refer to table in question #20 for the ingredients to be used in this syrup!

. STIRRING WITH HEAT (Syrup USP)

 -

.

1.      add Sucrose and preservatives to boiling water, then cool and mix with dissolved actives

2.      .stir with sylverson mixer

3.      add all other ingredients (colour,flavour,pH adjust)

4.      filter using a filter press

5.      fill into bottles

3.1.      .

4.6.    .

5.7.    .

6.8.    .

7.9.    .

                                                                                                                                                (10)

Question #22

List four (4) USP methods for Sterilization. List an item that could be sterilized with the method

1.      .Steam ¨C injections, metal tubes

2.      .dry heat- empty glass containers                                                                                                                       

3.      .filtration- injections, nasal/ophthalmic drops

4.      .ionizing radiation- disposable medical devices (eg. filters

5.      filling using aseptic technique ¨C (eg. blow fill seal ampoules in ¡®sterile¡¯ environments)                                                                                                                                 (8)

 

Question #23

What are the two main differences between a Syrup and a Suspension?

a)      (Syrup).concentrated colutions of sugar and contain solvents that solubilize insoluble drugs

.

b)      (Suspension).particles are suspended in the solution. Particles should settle slowly but readily disperse on gentle shaking of the container

.

                                                                                                                                                (4)

Question #24

What is the filter size that must be used to produce a sterile solution?

.               0.22 Micron

What would you do to prolong the use of this Sterile Filter?

.prefilter solution in 0.45micron filter, filter solution in highly sterile environment, use cross flow method instead of dead-end method

.

                                                                                                                                                (2)

Question #25

Complete these tables by listing the use of the ingredient in these formulations

 

DIAZEPAM Tablets

INGREDIENTS

PURPOSE IN FORMULATION

Diazepam

API

Lactose

Diluent/binder

Cornstarch (3 uses)

Diluent/lubricant/glidant

Microcrystalline Cellulose

Distegrant

D&C Yellow #10

Color

Sunset Aluminum Lake 40%

Color

Magnesium Stearate

Lubricant

 

 

CALCIUM TABLETS

INGREDIENTS

PURPOSE IN FORMULATION

Calcium Carbonate

Ingredient for coating (subcoating stage)

Crosscarmellose Sodium

Disintegrant

Sodium Lauryl Sulfate

Disintegrant

Magnesium Stearate

lubricant

Hydroxypropyl Methyl Cellulose

Polymer for aq coating

Poly Dextrose

Increases polymer permeability for coating

Polyethylene Glycol

Plasticizer for coating

Titanium Dioxide

Color (grossing stage in coating)

Brilliant Blue

Color

D&C Yellow # 10

Color

Carnauba Wax

Glossy finish/polish coating

 

                                                                                                                                                (8)

 

Question #26

How would you produce this pink oil in water cream? List the stages of manufacture, temperature, conditions order of addition of ingredients.

 

 
           

1.       Stearic Acid (Triple pressed)                  0.760Kg

2.       White Beeswax                                  13.590Kg

3.       Spermacetti                                          7.550Kg

4.       White Petroleum Jelly                          15.100Kg

5.       Mineral Oil                                           56.850Kg

6.       Borax  (Emulsifying Agent)                     1.880Kg

7.       De-ionized water                                 13.270Kg

8.       Rose Oil Concentrate (Perfume)            0.010Kg

9.       Red Dye #40                                                0.010Kg

1.      .melt 1-4 together in jacketed kettle

2.      .heat to 65 Deg C

3.      .add 5

4.      .dissolve 6 in 7, heat to 65 Deg C

5.      add red dye #40 to water phase

5.6.    .slowly add oil phase to water phase, and mix continuously

6.7.    .cool to 25-30Deg C

7.8.    .add perfume

8.9.    .   mix

                                                                                                                                    (8)

Question #27

A tablet with the formula listed below has to be film coated (Aqueous Film).

At present, the friability tends to be high after compression - especially in winter. What precautions could be taken to ensure success of the final product. Without changing any raw material? 

INGREDIENT                                                 Per Tab.

Acetylsalicylic Acid USP (Crystals)                300 mg

Caffeine USP  (Powder)                                    30 mg

Starch N.F.      (9-13% moisture)                        35mg

                                                                      365 mg

1.      .ensure correct speed of drying to prevent sticking/picking

2.      .control pan RPM, supply air humidity, solution delivery rate

3.      .prevent entrapped air in tablet

4.      .ensure correct(expanded) core temperature before spraying                                                                                                                                  (4)

                                                                                   

Question 28

 Suggest a formula for a CLEAR aqueous film coating solution for this product. List the type and proper name of the ingredients.      

1.      .polymer- HPMC ( and maybe poly Dextrose to help permeability)

2.      .plasticiser- polyethylene glycol

3.      .pigment- aluminum oxide

4.      .water                                                                                                                          (8)

                                               

Question 29

Why is Yellow Petroleum Jelly preferred in the manufacture of ophthalmic ointments?        (2)

.white always contain some residual sulfite from bleaching process

 

 

 

 

Question 30

List three uses for transdermal patches. List BOTH the Medicinal use with the active ingredient.                 

1.      .fentanyl- 72hr systemic delivery of potent opiod analgesic

2.      .nicotine- continuous&systematic delivery of nicotine as aid to cessation of smoking

3.      .Scopolamine- controled release of scopolamine for continuously 72hrs. prevents nausea from motion sickness                                                                                                                (6)

Question 31

Acetaminophen Tablets 500mg. These tablets were made in a fluid bed by spray granulation and fluid bed drying.. On compression the tablets started splitting and capping.

(Tablet Formula per tablet)

1.      Acetaminophen                     500mg

2.      Hydroxy-propyl cellulose       5mg

3.      Magnesium Stearate                           2mg                         

4.      Croscarmellose Sodium         2mg

1 is granulated with a mixture of 2 dissolved in sufficient water to allow a good spray for spray granulation. 3 & 4 are added to the mix after the granulation has been screened and dried.

What could have caused this problem?  List at least 3 causes in granulating and 3 in compressing.                                                                                                                                                         

1.       granulation

2.       .too little liquid

2.3.    .over heating / drying

3.4.    .insufficient drying, too much liquid, too much mixing

4.5.    .incorrect nozzle height

5.6.    .Compressing

6.7.    .excessive compression pressure

7.8.    .too rapid expansion on ejection

8.9.        .under weight/ thickness

10.     air entrapment in granules                                                                                                                                                                                          (6)                                                                                                                                                                                                                         

 
Question 32

The formula from Question 31 is encapsulated - during encapsulation, the bottom of the capsules dented.

 List three possible causes for this.

1.      .compression pressure too high

2.      .doser out of centre to bodies

3.      .    too much wear in cap bushings

(3)

 

Question 33

Metoprolol Tablets compressed as a capsule shaped tablet with a full bisect are breaking in the coating pan. Some cores are soft, others, comply with compression specifications. Dissolution and all other tests are acceptable

Tablet Formula                                  Per Tab                      Coating Formula

Metoprolol  USP                                   100mg                        Hydroxypropyl methyl cellulose

Lactose  NF                                            60mg                       Polyethylene Glycol

Microcrystalline cellulose                        30mg                       Blue Dye Lake #2       

Cab-o-Sil                                                  2mg                        Purified Water

Croscarmellose Sodium                           2mg

Magnesium Stearate                               5mg

 

What could be causing this problem - list as many causes that you can think of from compounding, granulation, compression and coating                                                      

1.      too little liquid in granulation

2.      layering or separation in hopper

3.      excess circulation causes too many fines

4.      pressure roll bearing or pivot worn

5.      inadequate circulation in compression stage

6.      air entrapment in granule from granulation stage

7.      humidity in compression area

8.      poor punch face conditions

9.      insufficient mixing time

10.    insufficient binder

11.    press running too fast                                                                                                      (10)

 

Question #34

On coating, the Blue coating fades in time. What could be the cause of this?                       (2)

1.      1.It has different soluability characteristics.

2.      It might be light sensitive

 

 

Question #35

Name three (3) binders used to manufacture tablets. What is it about the physical size or shape of the material that makes it an effective binding agent?

1.      .microstalline cellulose ph102 ¨C many empty places inside structure for material to enter

2.      .dicalcium phosphate- porous

3.      .powdered cellulose- stacked matrix of flakes allow material to get trapped inside                                                                                                                                      (6)

 

Question #36

Name three (3) disintegrating agents used to manufacture tablets. What is it about the physical size or shape of the material that makes it an effective disintegrating agent?

1.      .croscarmellose sodium- worms like- brings water to center of tablet from exterior

2.      .starch- porous and varying size, allows water to enter tablet

3.      .                                                     crospovidone- porous and allows water to enter tablet                                                                            (6)

 

Question #37

Using the guidelines of - ¡°Ingredients required in a Mix¡± - devise formulations for the following products. Each formulation must contain:

1.      Active Ingredient

2.      Binder (If required)

3.      Filler (If required)

4.      Glidant  (0.5-1%) (If required)

5.      Lubricant  (0.5-1%) (If required)

6.      Disintegrant. (If required) (As per Raw material listing ¨C 10% for Starch, 4-8% modified Starch, 0.5-2% Super Disintegrants)

You can make the product up to any weight required BUT REMEMBER smaller is better. In each case, list your actives and inactives ¨C list the inactives by their property e.g. Glidant etc.

1.      A tablet (to disintegrate) containing 500 mg of Acetaminophen, 30 mg of Caffeine and 8 mg of Codeine

2.      A tablet (to be coated) containing 300 mg of Ibuprofen ¨C List some coating Ingredients.

3.      A tablet (to chew or dissolve) containing 250 mg of Ascorbic Acid (Vitamin C)      

 

Fill in your answers in the tables below. You do not have to use all the lines in the table to create a tablet ¨C IF YOU ONLY NEED 3 INGREDIENTS ¨C USE 3 LINES!

DISINTEGRATING TABLET

 

INGREDIENTS

PURPOSE IN FORMULATION

Estimated QUANTITY PER TABLET

ACETAMINOPHEN

ACTIVE INGREDIENT

500 mg

Codeine

Api

8mg

Caffeine

Api

30mg

Magnesium stearate

Lubricant

7mg

Crosscarmellose sodium

Disintgrant

7mg

Starch

Binder/filler

100mg

Cab-o-sil

Glidant

7mg

 

 

 

 

 

TOTAL 650 ¨C 900 mg

(12)

TABLET TO BE COATED LIST SOME COATING INGREDIENTS!

 

INGREDIENTS (Core)

PURPOSE IN FORMULATION

Estimated QUANTITY PER TABLET

IBUPROFEN

ACTIVE INGREDIENT

300 mg

croscarmellose sodium

Disintegrant

4.5mg

Magnesium stearate

Lubricant

4.5mg

Cab-o-sil

glidant

4.5mg

Starch

Filler/binder

140mg

 

 

 

 

 

 

INGREDIENTS (Coating)

 

 

HPMC

Polymer

10mg

Glycerine

Plasticizer

1mg

Aluminum oxide

dye

5mg

 

 

 

 

 

 

 

 

TOTAL 450-500 mg

(12)

CHEWABLE TABLET

 

INGREDIENTS

PURPOSE IN FORMULATION

Estimated QUANTITY PER TABLET

ACSORBIC ACID

ACTIVE INGREDIENT

250 mg

Guar gum

Thickener/stabilizer

50mg

Aspartame

Sweetener

20mg

Microcrystalline cellulose

Binder/ dispersing agent

25mg

Magnesium stearate

Lubricant

5mg

 

 

TOTAL 350 ¨C 450 mg

 

(12)

TOTAL 245

Grades:

A+     90 % to  100%

A       80 % to  89 %

B+     75 % to  79 %

B       70 % to  74 %

C+     65 % to  69 %

C       60 % to  64 %

D       55 % to  59 %

F         0 % to  54 %