sdma - synhydrid® › cphi_europe › syn… · dextromethorphan hoffmann la roche antitussive...

SDMA - SYNHYDRID®

New developments in selectivity

Production, supply & technical support of Synhydrid®

Chematek SpAChematek has been the leading name in global fine chemical since its foundation in 1980.Currently the company has several offices in strategic locations all over the world.

The first Synhydrid batch was synthesized in1971. In spring 2005, the work onconstruction of a modern, large and saferSYNHYDRID® production plant wascommenced at Lucebni in Czech Republic. Bythe end of 2006 the production plant withstate of the art technology and nameplatecapacity of 1200 Mt/year was fullyoperational. In July 2017 capacity has beenfurtherly increased to 1800 Mt/year.

2

What is Synhydrid®Sodium bis(2-methoxyethoxy)aluminumhydride

• CAS No. 22722-98-1• Also generically known as SDMA, Red-Al• 70% solution in toluene• Active species:

• Organometallic reducing agent• Well known and fully commercialised, well documented uses and handling on

large scale (ref Chematek – earlier presentation – available on request with full supporting data on handling, packaging, safety etc)

3

What is Synhydrid® • Generically known as SDMA (Acronym for the full chemical name)• SDMA is Branded “SYNHYDRID®”• It is probably best known for a number of classic transformations, and

for its ability to replace the more reactive and hazardous Lithium Aluminium Hydride (LAH)

• Historically, when Innovators developed API’s they tended to use LAH as the standard reducing agent for certain types of reaction, and it was not until full commercialisation, and often, generic manufacturers in different geographical locations found LAH extremely hazardous – (with numerous fires) – that an alternative cost effective and safer solution was sought…….

• It is well known and is used in API synthesis in many drugs, in F&F and Agchem AI’s as well as some performance based products

Synhydrid®

4

Key Reactions

From To

Amide Amine

Ketone Alcohol

Anhydride Alcohols

Imine Amine

Nitrile Amine

Acid Chloride Alcohol

Acid Alcohol

Ester Alcohol

ChematekSynhydrid®

5

Additionally:

Epoxide opening to Alcohol

Wikepedia - SDMA• SDMA is a safer substitute for LAH and related hydrides. • SDMA exhibits similar reducing effects, but does not have the

inconvenient pyrophoric nature, short shelf-life, toxicity or limited solubility of LAH.

• SDMA upon contact with air and moisture, reacts exothermically but does not ignite, and tolerates temperatures up to 200 °C.

• SDMA has unlimited shelf life Under dry conditions. • SDMA is soluble in aromatic solvents, whereas LAH is only soluble in

ethers.• SDMA solution, greater than 70 wt.% concentration in toluene is

commercially available,

• It is now well known and is used in API synthesis in many drugs, also in F&F and Agchem AI’s as well as some performance based products and is more economically effective than LAH

SDMA = Synhydrid®

6

Key current commercial uses

7

USE Innovator Therapy USE Innovator Therapy

Aglometine Servier Antidepressant Emtricitabine Emory - Gilead HIV

Alfentanil hydrochloride Piramal Enterprises Anesthesia Eprosartan GSK Antihypertension

Aliskiren Novartis Antihypertension Fesoterodine Schwartz Bladder control

Ambrox Firmenich Perfume Fingolimod hydrochloride Mitsubishi Tanabe Pharma Multiple sclerosis

Amphotericin B Bristol-Myers Squibb Infection, fungal Fluoxetine Lilly Antidepressant

Asenapine maleate Allergan Schizophrenia Fluvastatin Novartis Anticholesterol

Atomoxine Lilly ADHDGadoxetic acid disodium

saltBayer

Imaging, magnetic resonance

Buprenorphine Reckitt Benkiser Opiod dependancy Galantamine Bonnie Davis Alzheimers

Capecitabine Hoffmann La Roche Anticancer Gemcitabine Lilly Anticancer

Ceftobiprole medocaril Basilea PharmaceuticaPneumonia, Hospital-

acquiredIsavuconazonium sulfate

Astellas PharmaBasilea Pharmaceutica

Antifungal

Cinacalcet Amgen hyperparathyroidism Ivabradine hydrochloride Servier Angina pectoris

Citalopram Lundbeck Antidpressant Lamivudine GSK HIV

Cyproconazole Syngenta Fungicide Lanopepden GSK Antibacterial

Dapozetine Liily Premature ejaculation Latanoprost Pfizer Antiglaucoma

Darunavir Janssen Infection, HIV Levamisole hydrochlorideJanssen

Kyowa Hakko KirinCancer

Dextromethorphan Hoffmann La Roche Antitussive Lopinavir Abbott HIV

Desvenlafaxine succinate Pfizer Depression Lurasidone hydrochloride Sunovion Schizophrenia

Donepezil Easai Alzheimers Mecamyline Merck Antihypertension

Dorzolomide Merck Antiglaucoma Menthol Takasago F&F

Eletriptan Pfizer Migraine Mericitabine Roche HCV

Darunavir Janssen Infection, HIV Mirtazipine Akzo Antidepressant

Key current commercial uses

8

USE Innovator Therapy USE Innovator Therapy

Mosapride citrateSumitomo Dainippon

PharmaGastritis Sorbyl Acetate Suterra Pheromone

Moxifloxacin Bayer Antibacterial Sofosbuvir Gilead (Originator) Anti-Hepatitis C Virus

Naltrexone hydrochloride Bristol-Myers Squibb Opioid dependency SQ109 Sequella Inc Antibacterial

Nebivolol Janssen Antihypertension Sufentanil Janssen Analgesic

Nefopam hydrochloride Biocodex Pain Tapentadol Grünenthal Analgesic

Olanzipine Lilly Antischizophrenia Ticagrelor AstraZeneca Thrombosis, arterial

Orteronel Takeda Prostate Cancer Tofacitinib citrate Pfizer (Originator) Rheumatoid arthritis

Oxycodone Purdue Analgesic TolvaptanOtsuka Pharmaceutical

(Originator)Hyponatremia

Paclitaxel BMS Anticancer Trabectedin PharmaMar Cancer

Paroxetine GSK Anti depressant Tolterodine Pharmacia Incontinence

Pentazocine Sanofi (Astellas) Analgesic Trabectadin Univ. Illinois Antitumour

PeramivirGreen Cross

ShionogiInfluenza Treosulfan Medac Cancer

Phenserine Axonyx Alzheimers Venlafaxine Wyeth Antidepressant

Pitavastatin calciumKowa

Nissan ChemicalHypercholesterolemia Vernakalant hydrochloride Cardiome Antiarrhythmic

Reboxitine Farmitalia Antidepressant Vilazodone hydrochloride Allergan Depression

Ritonivir Abbott HIV

Romidepsin National Cancer Inst Anticancer

Salbutamol Allen & Hanbury Bronchodilator

Other reducing agents….

• SBH/LBH• SBH - Sodium Borohydride/LBH - Lithium Borohydride

• SBH/LBH with Lewis acids • DIBAL

• Diisobutyl Aluminium Hydride

• TBLAH• Tri-tButoxy Lithium Aluminium Hydride

9

Other reducing agents….• SBH/LBH

• Generally these are used in protic solvents, usually methanol, ethanol or with aqueous based systems.

• In this case there are probably other reasons to use these such as getting the product isolated easily from salts, or water soluble impurities.

• Synhydrid® cannot be used in protic or aqueous based systems for obvious reasons……it will react itself with the media.

• In the event that SBH/LBH is used in say, a glyme which is aprotic, then a direct switch is feasible.

• The cost difference is around 20-30% - but as the cost of Lithium is rising, certainly in LBH this has a high impact on cost :

• LiBH4 mwt = 21.78, Li = 6.94 – therefore is 32% of the cost, and it is obviously not part of Synhydrid®.

10

• SBH/LBH with Aluminium Trichloride• Over recent years, people have used Aluminium Chloride to strengthen

the activity of SBH (or LBH) in particular• There have been numerous fires reported! – consider what is happening

3 NaBH4 + 4 AlCl3 → 4 AlH3 + 3 NaBCl43 LiBH4 + 4 AlCl3 → 4 AlH3 + 3 LiBCl4

Also, Alane reacts with water to evolve copious amounts of hydrogen:

2AlH3 + 6 H2O → 2 Al(OH)3 + 3 H2

1. Alane is generated in-situ. 2. Alane decomposes violently with air and moisture.

11


• SBH/LBH with Boron Trifluoride/Trichloride• Even more recently, people have used Boron Trihalides to strengthen

the activity of SBH (or LBH) in particular by forming diborane in-situ• Again there have been numerous fires reported! – consider what is

happening3 NaBH4 + 4 BF3 → 2 B2H6 + 3 NaBF4

3 LiBH4 + 4 BCl3 → 2 B2H6 + 3 LiBCl4

Diborane also reacts with water to evolve copious amounts of hydrogen:

B2H6 + 6 H2O → 2 B(OH)3 + 6 H2

1. Diborane is generated. 2. This is a very flammable toxic gas. 3. It is a flame accelerator4. It Auto-ignition temperature is 38C (explosive limits 0.8 – 88%)5. It can be used as rocket fuel……… 12


• DIBAL - Diisobutyl Aluminium Hydride

• DIBAL has become a commercial item in the last decade or so.• Although DIBAL can be purchased commercially as a colourless liquid, it

is more commonly purchased and dispensed as a solution in an organic solvent such as toluene or hexane.

• DIBAL is normally used because of its selectivity• DIBAL can convert esters and nitriles to aldehydes (vs LAH which

reduces to alcohols). • DIBAL reduces α-β unsaturated esters to the corresponding allylic

alcohol• DIBAL is difficult to handle in flammable, low flash point solvents, reacts

explosively with water and can cause fires. 13


• TBLAH - Tri-tButoxy Lithium Aluminium Hydride

• Even more recently, the introduction of TBLAH, another selective reducing reagent has expanded options for the organic chemist.

• However, although comparable to DIBAL and Synhydrid®, it is just as difficult to handle as DIBAL, and nowhere near as easy to use as Synhydrid®.

• TBLAH is highly flammable.• TBLAH is highly reactive with air.• Again, any moisture, oxygen etc. will decompose it and form hydrogen gas.

14


Synhydrid®

• For over 50 years, SYNHYDRID® has been used around the world.• Its inherent stability, reactivity and ease of handling – even in area’s of high

humidity, make it the reagent of choice for organometallic reductions.• It is stable under normal conditions (provided it is made correctly!).• It does not form explosive mixtures upon treatment with water or air.• It is selective, and is comparable to DIBAL and TBLAH and is currently used in

many cases, to replace LAH and SBH/LBH (with added lewis acid), DIBAL and TBLAH.

• Many people are aware of the comparison with LAH and SBH, but few know the ability for SYNHYDRID® to be used to replace DIBAL and TBLAH. 15

Name LAH Synhydrid® DiBAL TBLAH

Structure

H available Four Two One One

Conc. 95% 70% 25% 26%

H (g/kg) 100.1 6.89 1.76 1.02

Comparison of reductants

16

Comparison of reductantsMoles (theoretical)

Synhydrid® LAH DiBAl TBLAHAcid chloride to alcohol 1 0.5 2 2

Acid chloride to aldehyde 0.5 0.25 1 1Acid to aldehyde 0.5 0.25 1 1

Aldehyde to alcohol 0.5 0.25 1 1

Alkene to alkane 2 1 4 4Alkyne to alkene 0.5 0.25 1 1

Amide to amine 1 0.5 2 2

Amino acid to amino alcohol 1 0.5 2 2Anhydride to diol 2 1 4 4

Carboxylic acid to alcohol 1 0.5 2 2Carboxylic acid to aldehyde 0.5 0.25 1 1

Ester to alcohol 1 0.5 2 2Ester to aldehyde 0.5 0.25 1 1

Imine to amine 0.5 0.25 1 1

Ketone to alcohol 0.5 0.25 1 1

Lactone to diol 1 0.5 2 2Lactone to lactol 0.5 0.25 1 1Nitrile to alcohol 1 0.5 2 2

Nitrile to aldehyde 0.5 0.25 1 1Nitrile to amine 1 0.5 2 2 17

Volume efficacy of Synhydrid®

• Consider the actual strength of solution of SYNHYDRID® vs competitive selective reducing agents – as SYNHYDRID® is ~3 times more soluble in solvents, then the volume utilisation in your reactor is much better

• So the reduction using SYNHYDRID® can be done more efficiently with bigger batch sizes and fewer batches – reducing overall labour and utility cost.

MWT % w/w Solution Density mls/mol

Synhydrid® 202.16 70 1.122 257

DIBAL 142.22 25 0.798 713

TBLAH 254.26 26 0.9 1087

18

Comparison of reductant volumeGrams reductant per mole substrate

Synhydrid® LAH DiBAl TBLAHAcid chloride to alcohol 289 20 1,136 1,954

Acid chloride to aldehyde 144 10 568 977Acid to aldehyde 144 10 568 977

Aldehyde to alcohol 144 10 568 977

Alkene to alkane 578 40 2,272 3,908Alkyne to alkene 144 10 568 977

Amide to amine 289 20 1,136 1,954

Amino acid to amino alcohol 289 20 1,136 1,954Anhydride to diol 578 40 2,272 3,908

Carboxylic acid to alcohol 289 20 1,136 1,954Carboxylic acid to aldehyde 144 10 568 977

Ester to alcohol 289 20 1,136 1,954Ester to aldehyde 144 10 568 977

Imine to amine 144 10 568 977

Ketone to alcohol 144 10 568 977

Lactone to diol 289 20 1,136 1,954Lactone to lactol 144 10 568 977Nitrile to alcohol 289 20 1,136 1,954

Nitrile to aldehyde 144 10 568 977Nitrile to amine 289 20 1,136 1,954 19

• Cost of SYNHYDRID® is significantly lower than DIBAL, TBLAH and LAH

• Volume of SYNHYDRID®is much lower than DIBAL and TBLAH – which means better throughput and lower cost…

• Hazards of LAH, DIBAL and TBLAH make SYNHYDRID® the preferred choice.

20

Comparison summary

• Ketone reduction e.g. in Salmeterol synthesis

• Other ketone reduction example e.g. Flavours & Fragrances synthesis

Classic Reductions of Synhydrid®

21

SDMACH3

OCH3

CH3

CH3

OHCH3

CH3


22

• Aldehyde reduction e.g. in Bosentan synthesis

• Nitroso reduction e.g. in Clopamide synthesis

• Acid reduction e.g. in Mirtazapine synthesis


23

• Ester reduction e.g. in Tolterodine synthesis

• Amide reduction e.g. in Venlafaxine synthesis

• Lactone FULL reduction e.g. in Ambroxan synthesis


24

SDMA

Alpha-Ambrinol

SDMAX=Cl, Br

• Alpha-Ambrinol synthesis: Halohydrin reduction / Epoxide opening

• Nitrile reduction e.g. in Heterocyclic aldehyde or amine formation

• Sometimes multiple reductions e.g. in Galantamine synthesis


25

X = O, S

• Bis Imide FULL reduction in Boceprevir synthesis:


26

• Bis Imide FULL reduction in Moxifloxacin synthesis:

SELECTIVITY & Synhydrid®

• For over 50 years, SYNHYDRID® has been used around the world, often replacing LAH in chemical synthesis and commercial API’s etc

• Its inherent stability, reactivity and ease of handling – even in area’s of high humidity, make it the reagent of choice for organometallic reductions.

• It is well known for reductions such as those discussed earlier, Ester to alcohol, amide to amine, nitrile to amine etc.

• We now wish to expand the knowledge and discuss selective reductions that SYNHYDRID® can be used for based on modification of the ligand to replace reagents such as DIBAL and TBLAH.

HOW WE MODIFY Synhydrid® & WHY

27

Donepezil• This is one of the first examples of an API with a reduction using “softening” of

SYNHYDRID®, (reducing the power), by replacing one of the two available hydrides by an amine

• A conversion of an ester to an aldehyde.

28

Reduction of Ketone -> Carbacyclin

29

Methyl myristate -> tetradecanal

• DiBAL is well known for partial reductions, e.g. conversion of esters to aldehydes

• Temperatures are generally very low• Handling of DiBAL has its issues• Yields are often far from satisfactory (44-88%)• Consider US 4983746:

• We have shown that modified SYNHYDRID® will complete the same reduction as DiBAL in higher yields, less extreme temperatures, less hazardous conditions and more cost effectively.

30

Methyl myristate -> tetradecanal• How?• Add the amine to reduce the activity of SYNHYDRID®, use 1 meq/mole

Synhydrid®• Inverse addition• 20°C

• Yields are ~90% +

31

Comparison Example: SDMA vs TBLAH vs DIBAL in Sofosbuvir synthesis

Lactone-to-Lactol reduction:

Reducing Agent Addition Solvent Temperature Time Product Yield

SDMA* = SDMA/TFE

Reverse DCM -10°C 1 h 76 %

TBLAH Reverse THF -10°C -15°C 3 h 63 %

DIBAL Reverse THF -78°C 6 h Poor conversion

DIBAL Reverse THF -20°C 0.5 h Degradation:lactone opening and debenzoylation

SDMA*

What does this mean?

33

• This opens up a whole new option for partial reduction• Better yields• Less extreme temperatures (-20C to +20C) vs -78C for DiBAL• Safer manual handling – no fires! • More cost effective• Better throughput• This means that a whole new list of targets become accessible with greater

ease and less cost!• The following slide identifies these API’s • Those highlighted in green are known to be reduced with SYNHYDRID® and

literature precedents are in the public domain

API’s with partial reductionsCalcifediol Sanofi Launched

Morphine sulfate Astra Zeneca Launched 1909

Travoprost Generic Launched 1963

1,25-Dihydroxyvitamin-D3 Launched 1978

Alprostadil Vivus Launched 1979

Vigabatrin Sanofi Launched 1989

Galantamine hydrobromide Takeda Launched 1995

Gemcitabine hydrochloride Launched 1995

Latanoprost Pfizer Launched 1996

Donepezil Eisai Launched 1997

Nebivolol Launched 1997

Simvastatin MSD Launched 1998

Desogestrel Merck Launched 1999

Bimatoprost Allergan Launched 2001

Ezetimibe Merck Launched 2002

Pitavastatin calcium Daiichi Sankyo, Recordati Launched 2003

Cinacalcet hydrochloride Amgen Launched 2004

Duloxetine hydrochloride Lilly Launched 2004

Clofarabine Genzyme Launched 2005

Romidepsin Celgene Launched 2006

Darunavir Janssen Launched 2006

Fesoterodine fumarate Pfizer Launched 2008

Lacosamide UCB Launched 2008

Asenapine maleate MSD Launched 2009

Saxagliptin BMS Launched 2009

Tapentadol hydrochloride Gruenenthal Launched 2009

Lurasidone hydrochloride Sunovion Launched 2010

Eribulin mesilate Eisai Launched 2010

Telaprevir Vertex Launched 2011

Fidaxomicin Merck Launched 2011

Ticagrelor Astra Zeneca Launched 2011

• The disadvantages of LAH are well known• Handling is extremely difficult due to its pyrophoric nature – there are many examples

in the public domain – both small:

• A researcher at X was seriously injured when reducing a substrate using lithium aluminium hydride (LAH) in tetrahydrofuran (THF). Shortly thereafter, at least two other accidents involving procedures using LAH and THF have been documented. Due to the inherent hazards of LAH and THF, researchers must thoroughly plan out experimental protocols and incorporate safety measure to mitigate the hazards of this procedure. We have consulted with an outside expert in these issues, and he has made a number of important safety recommendations for this procedure.

• And large

• LAH is often frequently used as a 1 Molar solution in THF

Why Synhydrid® vs LAH?

35

• Safety issues of LAH have been highlighted.

• SDMA, being more stable than LAH, can be more effective in terms of equivalents needed: often large excess of LAH is added to push the reaction as LAH is partially quenched over time.

• The solvent of choice is often important:

- LAH is often refluxed in THF (Boiling Point = 66°C) or Diethyl Ether (Boiling Point =34°C).

- SDMA reactions can be heated or refluxed also in Toluene (Boiling Point = 110°C). Toluene can be separated and recovered vs THF is water miscible.

This gives more flexibility on applicable temperature range, and together with higher solubility of SDMA in organic solvents, easier industrialization.

• SDMA reactions are often suitable to less extreme cooling (I.E. -78°C cooling that is often used for LAH).

36

Why Synhydrid® vs LAH?

• The ease of handling has been already pointed out.• The safety of SDMA compared to organometallic reducing agents has been highlighted.• The selectivity of the reactions has also been discussed.• Put all that aside (NOT THAT YOU SHOULD).• Compare volume efficacy and cost efficacy of the simplest reactions.

Why Synhydrid® vs DIBAL/TBLAH?

37

Why Synhydrid® vs others?

Note – assumes LAH is used in 1M solution rather than as a solid for obvious reasons!

38

Chose carefully – avoid….

39

Use SDMA!!!

SAFETY! COST EFFICACY

SELECTIVITY

+

+40

SOME PARTIAL REDUCTION APPLICATION EXAMPLES

41

Custom Developments

SDMA* = SDMA modified so as to be partially quenched or «softened»:

As we have already seen, SDMA can be partially quenched, so as to perform partial reductions:

Modified Synhydrid®

42

43

SDMA*

Example: partial reduction of Ester intermediate to Aldehyde:

Nebivolol

R1 = I.E.: Methyl

Further Synhydrid application examples

44

SDMA*= SDMA partially quenched or «softened»

45

Example: Nitrile reduction to Alchoolvia partial reduction to Aldehyde .

CH3

N

CH3

OH

DIBAL

SDMA*CH3

OH

DIBAL

SDMA

1)

2) H2OCH3

OH

DIBAL1)

2) H2O

CH3

H

O

46

DIBAL

SDMA*

CH3

N

Example: Macrocyclic Lactones as fragrances: Nitrile to Aldehyde partial reduction.


N

CH3

O

CH3

H

SDMA*

DIBAL

Ingredient in fragranceformulation.

1)

2) H2O


47

Example: Cyclolalkane Aldehydes from Nitriles.

DIBAL1)

2) H2O

SDMA*

Ox Cond.

48

Example: P-Menthane Aldeydes from Nitriles.



49

Example: partial reduction of Lactone to Lactol: Latanoprost .

DIBAL

SDMA*


50

Example: partial reduction of Lactone to Lactol: Simvastatin.

DIBAL

SDMA*


51

Example: partial reduction of Lactone to Lactol: Niraparib.

DIBAL

SDMA*


52

Example: partial reduction of Lactone to Lactol: Rolapitant.

LAH

SDMA*

KHMDS

1)

2)

53

Lactol-derived fragrances

SDMADIBAL

SDMA*


Example: Lactol-structured fragrances: Lactone-to-Lactol reduction.


54

Example: partial reduction of Ester to Aldehyde:Sunitinib Malate.

DIBAL

SDMA*

O

O

O

CH3

OH

H

OSDMA*

Citronella-like fragranceSDMA*= SDMA partially quenched or «softened»

55

Oxidation

Example: Citronella-like aldehyde fragrance synthesis by partial reduction of Ester to Aldehyde.

SDMA

LAH

O

OCH3

CH3

56

SDMA*

DIBALH

OCH3

N

CH3

1) NH2OH

2) NaOH

SDMA* = SDMA modified so as to be partially quenched or «softened».

Example: Cyclopentyl-Alkyl-Nitriles by reduction of Ester to Aldehyde.

CH3

CH3

CH2

CH2

H

O

CH3

CH3

CH2

CH2

OHCH3

CH3

CH2

CH2

O

O

R

57

SDMA

LAH

SDMA*

Terpenic aldehyde fragrance

Ooxidation

SDMA* = SDMA modified so as to be partiallyquenched or «softened»:

Example: Terpene flavorantsby reduction of Ester to Aldehyde.

58

SDMA

LAH

CH3CH3

CH2 CH3

OH

O

CH3CH3

CH2 CH3

O

H

CH3CH3

CH2 CH3

OH

SDMA*

DIBAL


Example: Lavandulic acid derivatives by reduction of Carboxylic Acid to Aldehyde and Alcohol.

O

O

O

CH3

CH3

OH

CH3

O

O

CH3

OH

CH3

HSDMA*

DIBAL


59

Example: Pyran Aldehydes from Esters

SDMA*

DIBAL

O

O

CH3CH3

O

CH3 H

CH3 NH

O

CH3

CH3


60

Example: Spilanthol synthesis: Ester to Aldehyde.

61

Example of Diastereoselective Synthesis:

Sirolimus synthesis: Lactone to Lactol.

DIBAL

SDMA*

1)

2) TBDMSCl, Imidazole


Safety , Selectivity , Cost !

We’re here to helpDr. Riccardo LIBORICommercial DirectorCHEMATEKT. +33 4 90 03 27 84M. +33 6 84 93 99 02Fax. : +33 9 70 60 04 [email protected]

mailto:[email protected]

sdma - synhydrid® › cphi_europe › syn… · dextromethorphan hoffmann la roche antitussive...

Documents