The reigning City player of the year has had his campaign marred by injury, only appearing for a full 90 minutes five times as his club look to retain their Premier League title.
Guardiola has acknowledged the unfortunate nature of De Bruyne’s absence and said that the problems have been caused by an initial knee complaint.
“It’s a muscular problem. We see day by day but he [De Bruyne] is not available tomorrow,” Guardiola said at his press conference before Wednesday’s key match against City’s local rivals.
“Unfortunately he was injured and then another one and then another one.
“He had two or three muscular problems as a consequence of his knee.”
The former Barcelona and Bayern Munich coach suggested that fixture congestion in England was partly to blame for his midfielder's woes, but expressed his hope that the player could make a return before the end of the season.
“Unfortunately, in England you don’t have time to make preparations, the best way is to have a full preseason," added Guardiola.
“We have to pay more attention to the little details as we go forward.
“Now we have to see if he can play one or two more games before the end of the season and then have a good pre-season.
“He has a lovely family so his life is well-organised. We’re going to speak with him, the doctors and the physios to make sure he is safe and fit.”
Guardiola acknowledged the vital nature of the game against United, and every Premier League game remaining.
If City win all four games, they will win the league title for the second straight year, but losing any of them would hand the initiative to Liverpool.
Guardiola said: “Four games left and we have to win our four games to retain the title. It [Old Trafford] is not an easy place to go, but at the same time it is a nice place to go.
“We know exactly what we have to do and we’re going there for a big game.”