C 7 Capsules

Uy, Alyssa V. 2BPh

Chapter 7 – CAPSULES CAPSULES



made of gelatin, sugar & water



clear, colorless & essentially tasteless



colored with various FD&C and D&C dyes and made opaque by adding agents such as TITANIUM DIOXIDE

-

solid dosage forms in which one or more medicinal &/or inert



combination of colorants & opaquants to make them distinctive, many with caps & bodies of different colors

substances are enclosed within a small shell or container generally prepared from a suitable form of gelatin -

Depending upon their formulation, the gelatin capsule shells may be hard or soft.

GELATIN 

Characteristics: 

1.

May be swallowed whole by the patient

2.

May be inserted into the rectum for drug release & absorption from

4.

available in the form of a fine powder, a coarse powder, shreds, flakes, or sheets



Stable in air when dry but when become moist - subject to microbial decomposition

the site 3.

is obtained by the partial hydrolysis of collagen obtained from skin, white connective tissue & bones of animals

The contents may be removed from the gelatin shell & employed as



HGC contain 13-16% of moisture

a pre measured medicinal powder, the capsule shell being use to



extreme dryness - capsules may become brittle & crumble

contain a dose of the medicinal subs. (e.g. Theo-dur Sprinkle)



capsules absorbed moisture - a small packet of a dessicant material to protect against moisture

Elegance

5.

Ease of use



6.

Portability



dessicant use = DRIED SILICA, GEL, CLAY, ACTIVATED CHARCOAL

prolong exposure to high humidity can affect in vitro capsules

7.

Tasteless shell to mask the unpleasant taste/odor of the drug

dissolution - changes have been observed in capsules containing

8.

Permits physician to prescribe the exact medication

TETRACYCLINE, CHLORAMPHENICOL, NITROFURANTOIN

9.

Conveniently carried

10.

Readily identified

11.

Easily taken

12.

Tasteless when swallowed

13.

Commonly embossed or imprinted on their surface the

14. 15.



gelatin being a protein, is digested by PROTEOLYTIC ENZYMES and absorbed

Method used to track the passage of capsules and tablets through GIT to map

Available in variety of dosage strength

their transit time and drug release patterns

Provide flexibility to the prescriber & accurate individualized dosage

1.

More stable & longer shelf life

Scintigraphy - a noninvasive procedure that entails use of gamma

ray- emitting radiotracer incorporated into the formulation with

Packaged & shipped by manufacturers at lower cost less breakage than liquid forms

17.

gelatin is insoluble in cold water & soluble in hot water and in warm gastric fluid

manufacturer’s name and product code readily identified

for the patient 16.



gamma camera coupled to a data recording system 2.

When Scintigraphy is combined with pharmacokinetic studies, the resultant pharmacoscintographic evaluation provides information about the transit and drug release patterns of the dosage form as

Components of Capsules

well as the rate of drug absorption from the various regions of GT. 1.

Gelatin

2.

FD&C and D&C colorant

3.

Sugar

4.

Water  12-16% but may vary depending on the storage condition

5.

Sulfur dioxide (.15%) - prevent decomposition during manufacture

6.

Opaquants/Opacifying agent - titanium dioxide

HARD GELATIN CAPSULES

Uses of Pharmacoscintographic Pharmacoscintographic

1.

Determining whether a correlation exists between in vitro and in vivo

2.

Assessing the integrity and transit time of enteric coated tablets

bioavailability for immediate-release products through the stomach en route to intestines 3. 4.

Drug and dosage form evaluation in new product development  A separate technique using a pH-sensitive nondigestible

-

Also referred to as “DFC” (Dry Filled Capsule)

radiotelemetric device termed the Heidelberg capsule, the

-

Manufactured into 2 sections, the capsule body and a shorter

approximate size of a No. 0 gelatin capsule, has been used as a

cap

nonradioactive means

-

A recent innovation in capsule shell design is the Snap-Fit, Coni-

o

To measure gastric pH

Snap, Snap, and Coni Snap Supro hard gelatin capsules.

o

Gastric residence time

o

Gastric emptying time of solid dosage forms in fasting & nonfasting human objects

Capsule size

For human use, empty capsules ranging in size from 000 the largest

Drug absorption depends on a number of FACTORS

to 5 the smallest. Generally, hard gelatin capsule are used to encapsulate

between 65 mg to 1 gram HARD GELATIN CAPSULES 

1.

Solubility of the drug

2.

Type of product formulation ( immediate release, modified,enteric)

3.

Gastrointestinal contents

4.

Physiologic character & response

usually use in the extemporaneous compounding of Rx

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Empty capsule contain a significant amount of water that acts as

Manufacture of Hard Gelatin Capsule

 plasticizer for the gelatin film and is essential for their function. 

manufactured into 2 sections, the capsule body and the shorter cap



the 2 parts overlap when joined, with the cap fitting snugly over the

The standard moisture content specification of HGC is between 13-16% w/w.

open end of the capsule body 

shells are produced by chemical dipping of pins or pegs of the desired shape & diameter into a temperature-controlled reservoir of 

MANUFACTURING OF SOFT GELATIN CAPSULES

1.

Preparation of the fill material

2.

Shell-film formation

-

melted gelatin mixture 

the pegs made of manganese bronze, are affixed to plates, each

-

capable of holding up to about 500 pegs 



The shell mass is heated and melted as required. The

each plate is mechanically lowered to the gelatin bath, the peg

molten material is pressure-fed to extrusion dies via a

submerge to the desired depth & maintained for the desired period

metering pump, producing a film as the mass is extruded

to achieve the proper length & thickness of coating

onto a casting drum. The film thickness is precisely controlled using electronic positioning of the extrusion

the plate and the pegs are slowly lifted from the bath and the gelatin dried by a gentle flow of temperature-and humidity-controlled air



This process is specific to each product

when dried, each capsule part is trimmed mechanically to the proper

dies. 3.

Encapsulation

-

length and removed from the pegs, the capsule bodies and caps are

The resulting films are peeled from the casting drums and fed between a pair of rotating dies. A “FORM, FILL, SEAL”

 joined together

process is used that is identical to the one used to prepare traditional softgels. Capsule seals are formed by a combination of  heat and pressure. The freshly formed

1.

soft gels are then transferred to drying device.

Once raw materials have been received & released by Quality Control, the gelatin & hot demineralized water are mixed under vacuum in Stainless Steel

4.

Drying

Gelatin Melting System. 2.

-

After aging in stainless steel receiving tanks, the gelatin solution is transferred

portion of the water present in the shell. The semi-dried

to stainless steel feed tanks. 3.

capsules are spread onto trays and kept under controlled

Dyes, opacifants, and any needed water are added to the gelatin in the feed

temperature and humidity to complete the drying

tanks to complete the gelatin preparation procedure. The feed tanks are then

activity.

used to gravity-feed gelatin into the Capsule Machine 4.

From the feed tank, the gelatin is gravity fed to Dipper section. Here, the

5.

Inspection & Sorting

capsules are molded onto stainless steel Pin Bars which are dipped into the

-

gelatin solution. 5.

The Pin Bars pass through the upper and lower kilns of Capsule Machine Drying System. Here gently moving air which is precisely controlled for volume, temperature, and humidity, removes the exact amount of moisture fro m the

uniformity in weight, size and shape. Developing the Formulation Formulation and Selection of Capsule Size 

Once drying is complete, the Pin Bars enter the Table section which p ositions



In the Automatic section, capsule halves are individually stripped from the



Pins. 9.

The cap and body lengths are precisely trimmed to a ±0.15 mm tolerance.

10.

The capsule bodies and caps are joined automatically in the joiner blocks.

11. 12. 13.



Diluent or filler may be added to produce the proper capsule fill volume - ex. LACTOSE, MICROCRYSTALLINE CELLULOSE and STARCH



Disintegrants are frequently included in a capsule formulation - to assist the breakup and distribution of the capsule’s contents in the

Capsule quality is monitored throughout th e production process including size, moisture content, single wall thickness, and color.

stomach - ex. PREGELATINIZED STARCH , CROSCARMELLOSE, SODIUM

Capsules are sorted and visually inspected on specially designed R&J

STARCH GLYCOLATE

Inspection Stations. 14.

Preformulation Preformulation studies are performed to determine whether all of  the formulation’s bulk powders may be effectively blended together .

Finished capsules are pushed onto a conveyer belt which carries them out to a container.

The active and inactive components must be blended thoroughly to ensure a uniform powder mix  for the fill

the capsule halves for stripping from the Pins in the A utomatic section. 8.

The goal is to prepare a capsule with accurate dosage, good  bioavailability , ease of filling& production , stability and elegance

capsule halves. 7.

The dried capsules are inspected and sorted to ensure

Once dipped, the Pin Bars rise to the upper deck allowing the cap and body to set on the Pins.

6.

The first stage – a tumble drier  –removes a significant



Perfect capsules are imprinted with the client logo on high-speed

Empty capsule property

When necessary, particle size may be reduced by milling to produce particles ranging from 50 to 1000 µm



Drugs of lower dose or smaller particles are required, micronization is employed - 1 to 20 um particle size

Industrial Scale

-

The powder mix must be  free-flowing to allow steady passage of the capsule fill from hopper and into the capsule shell

-

Addition of lubricant or glidant - FUMED SILICON DIOXIDE , MAGNESIUM STEARATE, CALCIUM STEARATE , STEARIC ACID or TALC (about 0.25-1%) to

the powder mix enhances flow properties -

Magnesium stearate as lubricant , the water proofing characteristics

of this water-insoluble material can retard penetration by the gastrointestinal fluids and delay drug dissolution and absorption

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-

A surface active agent - sodium lauryl sulfate, is used to facilitate

Lubricants/gli dants

Talc, colloidal silicon dioxide

wetting by the Gastrointestinal fluids to overcome the problem

Wetting agent

Sodium lauryl sulfate

inserting tablets or small capsules into capsules are possible

Capsule opaquant

Titanium dioxide

Examples:

Filling Hard Capsules Shells 1. Use Punch Method

-

powder is placed on a sheet of a clean paper or porcelain plate

-

using spatula - formed into a cake having a depth of approximately one-fourth to one-third the length of the capsule body

-

then empty capsule body is held between the thumb and forefinger and punched vertically into the powder cake repeatedly until filled

Developing the Formulation Formulation and Selection of Capsule Size 

Gelatin capsules are unsuitable for aqueous liquids because water

softens gelatin and distorts the capsules, resulting leakage of the content 

retention of the liquid



-

with empty capsule in the loader tray, the tray placed on top of the filler unit

-

the loader inserts the capsules into the filling unit and is removed, and the top plate is lifted to separate the caps from the bodies

Some liquids or volatile oil do not interfere with the stability of the gelatin shells - may be placed in locking gelatin capsules to ensure



2. Feton capsule filling

-

the powder is placed on the unit and the capsule bodies filled the top plate is returned to the unit and the caps placed on filled capsule bodies

Eutectic mixtures of drugs - tends to liquefy - may be mixed with a

diluent or absorbent such as magnesium carbonate, kaolin or light

ProFill 100 - The ProFill 100 Capsule Filling Machine utilizes an advanced design

magnesium oxide to separate the interacting agents and to absorb

for fool-proof manual filling of two-piece capsules. With the ProFill 100

any liquefied material that may form

machine, there is no need for expensive capsule filling equipment and

Liquids are placed in soft gelatin capsules that are sealed during

electrical/vacuum connections.

filling and manufacturing Auger-Filling Principle Selection of capsule size is done during product development 

The choice is determined by requirements of formulation, including the dose of  the active ingredient and the density and compaction characteristics of the

Powder or granules are contained in mass flow hoppers with rotating augers



drugs.

Powder is fed continuously out of the hopper outlet due to the rotation of the auger.



Hard gelatin capsules are used to encapsulate about 65 mg to 1 g of powdered

Amount of powder fed into the body depends on the time capsule body spends underneath the hopper outlet and auger speed

material

- slower rotation increases the fill weight 

Tetracycline Capsules

Active Ingredient

Tetracycline hydrochloride 250 mg

Filler

Lactose

Lubricant/glida nt

Magnesium stearate

Capsule colorants

FD & C Yellow No.6, D & C Yellow no.10, D & C Red No.28, FD & C Blue No.1

Capsule opaquant

Titanium dioxide

Acetaminophen With Codeine Capsules

Active ingredients

Vibration-Assisted Filling 

Capsules are placed under the powder bowl



Powders or granules pass through the bowl’s mesh flow with help of  vibration



Bodies are filled to maximum plus more on top



Spring-loaded plunger compresses the powder inside the capsule body to make a firm plug

Acetaminophen 325 mg,



A scraper removes the powder outside the turn table bores

Codeine phosphate 30 mg



Capsule bodies are pushed upwards to be closed

Disintegrant

Sodium starch glycolate

Lubricant/glida nts

Magnesium stearate, stearic acid

Capsule colorants

D & C Yellow No. 10, edible Ink, FD & C Blue No.1 (FD & C Green No.3 and FD & C Red No. 40)

Diphenhydramine Diphenhydramine Hydrochloride Hydrochloride Capsules

Active ingredient

Diphenhydramine HCl 25 mg

Filler

Confectioner’s sugar

Filling of Pellets

1.

Double Slide Method 

Pellets flow from pellet machine to dosing chambers



Dosing slide is closed to separate dosing chamber and pellet magazine

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

2.

Outlet slides open

4.

Dissolution Test for capsules

5.

Weight Variation 

Vacuum-assisted Method

Hard Capsules - 10 capsules are individually weighed & the content



Dosing tube enters pellet bed

removed. Empty shells are individually weighed & the net weight of 



With the help of vacuum, the pellets are sucked into the

the contents calculated by subtraction 

dosing tube

Soft Gelatin - the gross weight of 10 intact capsules is determined



Excess pellet are scraped off the end of the dosing tube

individually. Then each capsule is cut open & the contents removed



Dosing tube is lowered and pellets released into capsule

by washing with suitable solvent. The solvent is allowed to evaporate

body

at room temperature over about 30 minutes. The individual shells are weighed and net contents calculated. 6. Content Uniformity 

Filling of Tablets

85-115% of the label claim for 9 of 10 dosage units assayed with no unit outside the range of 70-125% of label claim



 



Dosing slide, which can accommodate exactly 1 tablet, moves underneath tablet feeder Slider moves over the capsule body where tablet simply drops into it If properly filled, the pin dropped into the capsule body will have limited movements, the horizontal bar connected to the pin touches the sensor If not properly filled, horizontal bar will switch the sensor indicating incorrect filling. Empty capsules can be detected and eliminated from the product.

7.

Content Labeling Requirement 

all official capsules must be labeled to express the quality of each active ingredient in each dosage unit

8. Sta bility Testing 

to determine the appropriate conditions for storage and the  product’s anticipated shelf life

9. Moisture Permeation Test





Capsule Sealing

determined by packaging the dosage unit together with a colorrevealing dessicant pellet, exposing the packaged unit to known

1. 2.

Tamper evident  capsules by sealing the joint between the 2 capsule

relative humidity over a specified time, observing the dessicant

 parts

pellet for color change (indicating absorption of moisture) &

Distinctive looking capsules by sealing them with colored band of 

comparing the pretest & posttest weight of the package unit

gelatin (KAPSEALS). If removed, the band cannot be restored w/o Inspecting, Counting, Packaging, and Storing Capsules

expert sealing with gelatin 3.

Through a heat welding process that fuses the capsule cap to the



should have a uniform in appearance

body through the double wall thickness at their juncture - distinctive



defective capsules should be rejected

ring around the capsule where



capsules may be counted manually or automated equipment



containers are then mechanically capped, inspected visually or

heat welded

Ex.: Weld’s gelatin seal 4.

electronically, labeled, and inspected once more.

Liquid wetting agent that lowers the melting point in the contact 

areas of the capsul e’s cap and the body using low temperatures (40-

packaged in glass or in plastic containers

0

45 C) 5.

Lightly coating the inner surface of the cap with a warm gelatin

Oral Administration of Solid Dosage Forms

solution immediately prior to placement on the filled capsule body. 

The capsule sealing process of  banding ( Kapseals, Quali-caps) has been utilized 

for a number of years. In this process, two capsule parts are sealed with

without water is dangerous because of the  possibility that will lodge in the esophagus . Esophageal ulceration can occur with dry ingestion

gelatin or polymer band at the seam of the cap and body.

of tablets and capsules, particularly taken just before bedtime

Recently , a tamper resistant seal on hard gelatin capsules was developed in 

which the contact areas of the cap and body are wetted with a mixture of  0

placing the dose upon tongue & swallowing it w/ a glassful of water or beverages

example of drugs of greatest concern are: ALENDRONATE SODIUM , ASPIRIN , FERROUS SULFATE , NSAID, POTASSIUM CHLORIDE , & TETRACYCLINE

0

water and ethanol and then thermally bonded at 104 to 113 F. 

the proper administration of alendronate sodium tablets ( FOSAMAX) calls for tablets to be taken with full 6 or 8 ounce glass of plain water

Compendial Requirements for Capsules

upon rising in the morning or half an hour before taking any food  –

1. Added Substances Substances

to prevent local irritation of esophagus

a.

Harmless in the quantities used

b.

Do not exceed the minimum amounts required to provide their

Some Medications Commercially Prepared Into Soft Gelatin Capsule

intended effect

1.

Acetazolamide - Diamox = Carbonic anhydrase inhbitor

Do not impair the product’s bioavailability, therapeutic efficacy or

2.

Cyclosporine - Sandimmune = Immunosuppressive

safety

3.

Cyclosporine - Neoral =Immunosuppressive

Do not interfere with requisite compendial assays & test

4.

Digoxin - Lanoxicaps = Cardiac glycoside

5.

Ethosuximide - Zarontin = Anticonvulsant

6.

Ranitidine HCl - Zantac GELdose = Histamine H2 receptor inhibitor

c. d.

2. Containers for for dispensing 

tight, well closed & light resistant containers depending on the item

3. Disintegration Disintegration Test for Capsules 

the capsules are placed in the basket rack assembly, which is

Process Capsule Filling

1.

Milling /Sieving of all Ingredients

fluid at 37 C and observed over the time described in the individual

2.

Blending

monograph

3.

Capsule Filler

4.

Capsule cleaner/deduster

immersed 30 times per minutes into a thermostatically controlled 0

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5.

Capsule injection screen

6.

Capsule check-weighing system/reject

7.

Finished capsules

8.

Packaging

Advantages Of Coni-Snap

1. The tapered rim avoid telescoping 2. The indentations prevent premature opening 3. The grooves lock the two capsule parts together after the capsule has been filled

Empty Hard Gelatin Capsule Physical Specifications

1.

Tapered rim

Density

2.

Grooves

1.37

960

3.

Indentations

23.30

0.95

665

7.65

21.70

0.68

475

1

6.91

19.40

0.50

350

2

6.35

18.00

0.37

260

3

5.82

15.90

0.30

210

Outer Diameter

Height or Locked

Actual Volume

(mm)

Length (mm)

(mL)

000

9.91

26.14

00

8.53

0

Size

Typical Fill Weights (mg) 0.70 Powder

Preparation Of Filled Hard Gelatin Capsules

1.

Developing & preparing the formulation & selecting the size of  capsule

4

5

5.31

4.91

14.30

11.10

0.21

0.13

145

2.

Filling the capsule shell

3.

Cleaning and polishing the filled capsules

90

SOFT GELATIN CAPSULES

-

aka Soft Elastic Capsule

-

prepared from shells of gelatin from w/c glycerin or a polyhydric alcohol and as sorbitol has been added to render the gelatin elastic

or plastic like. -

The gelatin is plasticized by the addition of  glycerin, sorbitol or polyol. The shell may contain preservatives preservatives to prevent from fungi.

A soft gelatin capsule has a seam at the point of closure of the 2 halves, and the contents can be liquid, paste or powder Methods For commercial Manufacture Of Soft Gelatin Capsule

1.

Plate-Process. A warm sheet of prepared gelatin is laid over the

lower plate and the liquid is poured on it. A second sheet of gelatin is carefully put in place and this is followed by the top plate of the mold. The set is placed under the press where pressure is applied to form the capsule which is washed off with a volatile solvent to remove any trace of oil from exterior. 2.

Rotary Die Process. The rotary die machine is a self-contained unit

capable of continuously & automatically producing finished capsules from a supply of gelatin mass and filling material which may be any liquid, semi- liquid, or paste that will not dissolve gelatin. Two continuous gelatin ribbons , which the machine forms, are brought

into convergence between a pair of revolving dies and an ejection wedge.

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3.

Norton Capsule Machine. This machine produces capsule



completely automatically by leading two films of gelatin between a

4.

Two ribbons can be sealed and cut along the slightly raised rims of the dies for filling

set of vertical dies . These dies as they close, open, and close, are in



The capsule is washed with organic solvent and pre-dried

effect a continual vertical plate forming row after row of pockets



Advantages:

across the gelatin film. These are filled with medicament and as they

-

progress through the dies, are sealed, shaped, and cut out of the film

-

different colors for both sides

as capsules which drop into a cooled solvent bath.

-

wide variety of fills

capsules can have all kinds of shapes & sizes

Accogel Capsule Machine. Or Stern machine, uses a system of rotary



Disadvantages:

dies but is unique in that it is the only machine that can successfully 

-

high amount of shell waste material

 fill dry powder into a soft gelatin capsule .

-

longer drying time compared to Globex Method

Application Of Soft Gelatin Capsule

Check-weighing Based on Gravity Flow 

Liquid which may be encapsulated encapsulated into soft gelatin capsules include:

1.

Water immiscible, volatile & nonvolatile liquids such as vegetable & aromatic oils, aromatic and aliphatic

The capsules are fed from the hopper by means of a drive mechanism and size-dependent guiding plate onto the weighing cell.



After check weighing, the capsules are classified into correctly and incorrectly filled ones

hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohol & organic acids. 2.

Water miscible, nonvolatile liquids such as polyethylene glycols, and nonionic surface active agents as polysorbate 80

3.

Cleaning and Polishing 

Water miscible and relatively nonvolatile compounds, as

small numbers by rubbing them with a clean gauze or cloth.

propylene glycol and isopropyl alcohol, depending upon factors



as concentration used and packaging conditions.

Ethychlorvynol (Placidyl)

2.

Demeclocycline HCl ( Declomycin )

3.

Chlortrianisene (TACE)

4.

Digoxin (Lanoxicaps)

5.

Docusate calcium (Surfak)

6.

Vitamin E

Manufacturing Manufacturing Soft Gel Capsules

1.

Globex Method 

the capsules as they exit the equipment. Or using Accela-Cota



Shell forming solution is pumped through the outer capillary of  the concentric double capillary



The soft capsules are then immersed in a cooling bath of about o



apparatus. Inspecting, Counting, Packaging, and Storing Capsule

1.

2.

Using Sanitary Counting Tray

(a)

placing units from stock package onto tray,

(b)

counting and transferring units to trough,

(c)

returning excess units to stock container,

(d)

placing counted units into prescription container.

Using Mini-Counter II

-

Filling is pumped through the inner capillary of a concentric double capillary

On a large scale, many capsule-filling machines are affixed with a cleaning vacuum that removes any extraneous material from

Drugs commercially prepared in Soft Gelatin capsules:

1.

On a small scale, capsules maybe cleaned individually or in

Small automatic tablet and capsule counting and filling apparatus.

3.

Using Versacount Model

4.

Automatic tablet and capsule counting and filling apparatus.

Using large Merill filling machine -

fills 16 bottles with 200 tablets each at one time, a flipper gate in the

4 C (usually liquid paraffin)

upper manifold directs the tablets into one row of bottles while the

Cooling bath ensures immediate sol-gel transformation, hence

other filled row is evacuated and a new row of bottles moves into place.

formation of flexible yet firm robust outer film. 

Soft capsules are collected, washed with organic solvent to remove residues of cooling liquid & gently dried at a relative humidity of 20% in infrared tunnels.



Advantage: production of  seamless capsules which are tamperevident and free of contamination or entrapped air.

2.

Rotary Die Method  

Shell materials are converted into liquid state. Plasticizers and other additives are added to the liquid shell materials.



Shell ribbons are formed and passed through cooling bath. This transforms sol state to gel state.



After cooling bath, capsules are lubricated on either side with liquid paraffin or vegetable oil.



The ribbons are guided to counter-rotating rolls containing sharp- edged dies



Each die cavity has the size and shape of half of the capsule



Die rolls are pressed together with pressure

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