정밀화학공정의 분리•정제 scale-up 기술

한국화학연구원Kilo-Lab

김광제

정밀화학산업

고부가가치, 소량다품종, 기술집약적 산업고부가가치, 소량다품종, 기술집약적 산업

석유화학산업

의약, 농약기능성 화장품식품첨가제

생리활성 물질 기능성 화학소재

감광제 및전자재료형광물질첨가제

BTITNT

기반 화학소재, 대량생산, 장치산업기반 화학소재, 대량생산, 장치산업

전체 화학산업에서의 정밀화학 산업의 비중

28 %

우리 나라

선진국

60 – 80 %

정밀화학 연구개발 발전 방향

80 – 2000 년 00 – 20 년대60 – 70 년대

석유화학 BT•NT•IT – basedFine chemical

정밀화학

기관별 이용현황(1999-2001)

화학(연) Kilo-Lab의정밀화학 제품 용도별 이용 현황

(횟수, 2001년 기준)

68건

의약 중간체

농약 중간체

기능성 화장품 원료

반도체/전자재료

첨가제

접착제/도료

계면활성제

흡착제, 기타

2연구소/ 대학

14벤처기업

722중소기업

5대기업

내부(7)

(43)외부

정밀화학 공정의 분리•정제 기술

출발 물질 반응

여과 추출 흡수/흡착

증발

재결정 크로마토그래피증류

건조 고체 제품액체 제품

분리• 정제 scale-up 고려사항

여과- 재질 : 내식성, 내화학성( PTFE-lined, stainless steel 등) - 온도 : 고온, 실온, 저온(jacketed filter, cooling room 등) - 형태 : Nuche type, centrifuge, line filter, filter dryer,

press filter, drum filter 등- 진공, 가압

추출- 재질 : 내식성, 내화학성(glass, stainless steel, PTFE-lined)- 교반기의 impeller 형태 : turbine, propeller, anchor 등- separation point 확인 여부 지점을 투명재질로

흡수/흡착

- 재질 : 내식성, 내화학성(glass, FRP 등)

- 반응의 부산물(HCl. Cl2, SO2, HBr 등) 중화, 흡수 처리

⇒ gas scrubber

- VOC를 제거하기 위한 흡착탑

- 중화열, 흡수열, 흡착열을 고려한 condenser/냉각기

(물질수지, 열수지 데이타)

증발- 재질 : 내식성, 내화학성- 증발 잠열, 진공도, cold trap 등- 열안정성 : Thin Film Evaporator

증류- 재질 : 내식성, 내화학성- 조업 형태 : 진공 회분증류, 상압 연속증류- 열안정성 : molecular distillation- computer software의 simulation 결과 활용

재결정- 재질 : 내식성, 내화학성- 용해도 차이에 의한 분리 : 냉각, 증발, 용매선정

크로마토그래피- 충진물질 선정(silica, chiral 분리용 등)- 운전 압력 : 고압, 중압, 상압- 용매 취급 주의(특히 hexane)

Table Common solvent for extraction of aqueous solutions

Easily dried, low boiling point, low density

Inflammable

Poor solvent for polar organic materials

Hydrocarbons or other non-polar material

0.6336°N-pentane

Most polar common solvent which does not mix with water

Inflammable, absorbs large amount of water

Polar materials

0.9077°Ethyl acetate

Nonflammable, easily dried

Toxic, may form emulsion

General1.4961°Chloroform

CheapToxic, inflammable, prone to emulsion

Relatively non-polar substances

0.8880° Benzene

Nonflammable

Low boiling, easily dried

Slightly toxic, may form emulsion

General1.3441°Dichloromethane

Low boiling point

cheap, low viscosity

Low density

Inflammable

Absorbs water,

Forms peroxides

General0.7135°Ether

AdvantageDisadvantage

UseDensity

B.P.Solvent

Table Solvents for Recrystallization

Crystals from H2O dry, not flammable

Not for acid-sensitive cmpds,

Very toxic

may react with acids, bases;very flammable

very, very flammable

not flammable

not flammablenot flammable, highly toxic, cummulative poison

very flammable, highly

toxic cummulative poison

acetone, alcohols

water

water benzene

water

water

ethyl acetate

Water

ether

acetone

water,

water

hydrocarbons

ethanol

hydrocarbons

hydrocarbons,

ethylacetate

hydrocarbons, ethylacetate

Salts, polar cmpds

“

Polar cmpds

General

General

Polar cmpds & general

Low melting cmpds

General

Usually, low melting cmpds

General

Non-polar cmpds

Aromatic, cmpds

Aromatics,

hydrocarbons

100°

118°

82°65°78°

56°

35 °

77°40°

61°76°

80

111°

Water

Acetic Acid

Acetonitrile

Methanol

Ethanol

Acetone

Ether

Ethyl acetate

Dichlorome-thane

Chloroform

Carbon Tetrachloride

Benzene

Toluene

CommentsSuggested 2nd Solvent for Mixture

Common Usesb.p.Solvent

Scale-Up 기술• 시제품 생산• 공정개발공정개발 개념도

YesLabrunsO.K.?

Processdevelopment

lab runs

Synthesis author

WrittenLabprocedure

Scale production

pilot plant runsdata collection,tuning

Productiondemonstration

and tuning

Commercializationrequest

No

Rediscuss with author

공정 Scale-up 단계별 구분

5 – 20 liter 50 – 2000 liter 1 – 10 m33 liter

Full scaleLab Pilotbench

Kilo-Lab commercial plant

발주•설치기본설계 상세설계

엔지니어링생산자료 확보

운전•수정

Pilot Plant Basic Design

1. Process principle & description2. Design basis3. Material & heat balance4. Equipment & utility summary list5. Piping & Instrument diagram6. Control panel & electrical diagram7. Plot plan8. Operating manual9. Analysis manual10. Safety

Equipment data sheet, Piping & valve scheduleInstrument schedule

1. Process Principle & Description- Chemistry- Properties of reactant and product- process description

2. Design Basis- production capacity- operation day- feed specification- product specification

3. Material & Heat balance- drawing of PFD(process flow diagram)- table : stream number, component, temp., pressure,

heat flow, state

4. Equipment & Utility Summary

- equipment list : name, type, specification, material,

operation pressure, temp.

- utility summary : cooling water, steam, hot water,

hot or cooling medium, electricity, N2, Air

vacuum

5. Piping & Instrument Diagram- valve, pressure control, temperature control, flow control,

level control instrument, flow & line symbols

6. Control Panel & Electrical Diagram- single line diagram- control panel lay out digital control system

7. Plot plan- equipment layout- piping layout- structure

8. Operating Manual- preparation for operation- operation procedure- shut-down procedure

9. Analysis Manual- GC, HPLC, oxygen, moisture, NMR, etc.

10. Safety- MSDS, toxicity data

Pilot 설치 및 운전

Recommended vendor

Quotation analysis

Vendor selection

Procurement

Installation

Preliminary operation

Pilot test

Production

당국의 규제

• GMP란 우수의약품을 생산하기 위해서 ‘ 제조소의 구조,설비를 비롯하여 원료의 구입 ⇒ 제조 ⇒ 포장, 출하에이르기까지의 제조공정” 전반에 걸쳐 지켜야 할 요건을

규정한 것으로 Good Manufacturing Practice의 약자임

WHO : Good Practices in the Manufacturing and Quality Control of Drugs

미국 : Current Good Manufacturing Practice in Manufacturing, Processing, Packing or Holding of Drugs(cGMP)

영국 : Guide to Good Pharmaceutical Manufacturing Practice

한국 : 우수의약품 제조 및 품질관리기준(KGMP)일본 : 의약품의 제조관리 및 품질관리 규칙

GMP 적용범위BGMP

합성추출

출발물질

정제Crude product

원료의약품중간체

(출고)

원료의약품완제의약품

의약품 GMP

GMP 관리

1. Premises & Equipment2. Staff3. Process/Production4. Documentation5. Quality Control

구조설비 완비인위적 과오 최소

오염 방지

품질보증체계 수립

직원 교육

기준서 정비

GMP달성

Distillate분리공정 개발의 4 단계

Step 1: Define problem• want to separate A from B• complex mixture• No VLE data

A

Feed

BStep 2: Perform process studies• Do literature search for VLE• Do bench-scale screening tests• Lay out possible process

scheme• Do computer simulation• Optimize operating conditions• Determine parameters for pilot

test

Bottoms

Step 3: Perform pilot-plant test• Determine type of equipment needed• Determine size

Diameter, Number of stagesType of internals, Height of internal

• Determine operating parameters to run

Flow rates, Composition rangePressure and temperature

Distillate

Step 4: Scale up to commercial size• Scale up to commercial size• Determine

Type of internals, Height of internalsOptimum configuration, special design featuresFlows and compositions

Flow rate

Bottoms

평형조건과 가능한 분리기술

• Absorption and stripping

• Distillation• Stripping

x y

y

x

• Distillation• Extractive distillation• Liquid-liquid extraction

y

x• Azeotropic distillation• Extractive distillation• Pressure-swing distillation• Liquid-liquid extraction• Reactive distillation

y

x

Vacuum Distillation• low pressure• low temperature• little thermal stress• no thermal decomposition• better product quality

Applications for Vacuum Distillation

Heat Sensitive Products• Fine Chemicals• Food• Oil- and Fat- Industry• Recycling

Vacuum Distillation

Evaporator Types:• Pot Still• Thin Film(Wiped Film)• Molecular distillation(Shot Path)

Pot Still• batch process• long residence time• poor vacuum

Thin Film Evaporator

• short residence time• increased heat transfer

by turbulent film• continuous process• limited vacuum

Molecular Distillation Unit

• continuous process• short residence time• no pressure drop for

vapor• internal condenser• turbulent film

Molecular Distillation

• Operating pressure: fine vacuum ( 10-3 until 10 mbar )

• free path length• Langmuir Knudsen equation

m: distillate quantityp: pressureA: surface M: molecular weightT: temperaturek: constant

TMApkm ⋅⋅⋅=